CN107250110A - The noval chemical compound of (RET) inhibitor is reset as transfection - Google Patents

The noval chemical compound of (RET) inhibitor is reset as transfection Download PDF

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Publication number
CN107250110A
CN107250110A CN201580060784.XA CN201580060784A CN107250110A CN 107250110 A CN107250110 A CN 107250110A CN 201580060784 A CN201580060784 A CN 201580060784A CN 107250110 A CN107250110 A CN 107250110A
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phenyl
urea
trifluoromethyl
alkyl
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CN107250110B (en
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张玫
M·P·德玛蒂诺
H·S·艾达姆
H·A·关
秦东辉
吴成德
龚珍
杨海英
于海宇
张治柳
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GlaxoSmithKline Intellectual Property Development Ltd
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Abstract

The present invention relates to resetting the noval chemical compound of inhibitor of (RET) kinases, the pharmaceutical composition containing them, its preparation method and its purposes in the treatment alone or in combination as transfection, for intestines and stomach sensitiveness, motility and/or secretory normalization, and/or the belly patient's condition or disease, and/or relevant with RET dysfunctions or wherein regulation RET activity may have the treatment of following diseases for the treatment of benefit：The including but not limited to IBS (IBS) of all types, including diarrhea predominance type, constipation leading type or alternating bowel movement pattern, feature aerogastria, functional consitipation, functional diarrhea, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, Functional Esophageal Disorders, feature Depressed rats, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid carcinoma, undifferentiated thyroid carcinoma, papillary thyroid carcinoma, brain tumor, cavum peritoneale cancer, solid tumor, other lung cancer, head and neck cancer, glioma, neuroblastoma, Von Hipple Lindau syndromes and kidney neoplasms, breast cancer, carcinoma of fallopian tube, oophoroma, transitional-cell carinoma, prostate cancer, cancer at esophagus and Esophagogastric junction, cancer of bile ducts and gland cancer, and any malignant tumour with increased RET kinase activities.

Description

The noval chemical compound of (RET) inhibitor is reset as transfection
Invention field
The inhibitor of (Rearranged during Transfection, RET) kinases is reset the present invention relates to transfection Noval chemical compound, the pharmaceutical composition containing it, its preparation method and its purposes in the treatment alone or in combination, it is quick for intestines and stomach Perception, motility and/or secretory normalization, and/or the belly patient's condition or disease, and/or relevant with RET dysfunctions Or wherein regulation RET activity may have the treatment of following diseases for the treatment of benefit：The intestines of including but not limited to all types are easy Bowel syndrome (IBS), including diarrhea predominance type, constipation leading type or alternating bowel movement pattern, feature aerogastria, feature are just Secret, functional diarrhea, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, feature oesophagus Disease, feature Depressed rats, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, Hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid carcinoma, undifferentiated thyroid carcinoma, papillary thyroid Cancer, brain tumor, cavum peritoneale cancer, solid tumor, other lung cancer, head and neck cancer, glioma, neuroblastoma, Von Hipple- Lindau syndromes and kidney neoplasms, breast cancer, carcinoma of fallopian tube, oophoroma, transitional-cell carinoma, prostate cancer, esophagus and oesophagus Cancer, cancer of bile ducts and the gland cancer of stomach junction and any malignant tumour with increased RET kinase activities.
Background of invention
IBS (IBS) is a kind of common disease, and 10,1 or 20% individual is influenceed in developed country, and And be characterized in that abnormal bowel habits, aerogastria and internal organ hypersensitivity (Camilleri, M., N.Engl.J.Med., 2012,367:1626-1635).Although IBS etiology unknown, it is illness between brain and intestines and stomach, intestines microorganism to refuse letter Interference or increased inflammation caused by.Caused intestines and stomach change can influence normal enteron aisle to convey, so as to cause abdomen Rush down or constipation.In addition, in most of IBS patients, the sensitization of peripheral neverous system causes internal organ hypersensitivity or abnormality to be ached (Keszthelyi, D., Eur.J.Pain, 2012,16 bitterly:1444-1454).
Although IBS does not change life expectancy directly, its quality of life to patient has a great impact.Moreover, pin To health care related IBS and because worker's caused cap loss absent from duty can have significant financial cost (Nellesen,D.,et al.,J.Manag.Care Pharm.,2013,19:755-764).Extreme influence IBS minimal invasive treatments One of most important symptom of quality be splanchnodynia (Spiegel, B., et al., Am.J.Gastroenterol., 2008, 103:2536-2543).Suppress the molecular strategies of the related splanchnodynias of IBS by the quality of life of extreme influence IBS patient and reduction Associated expense.
Transfection reset (RET) be a kind of trk C EGFR-TK, its with respectively with co-receptor nerve Four kinds of neurotrophic factors of trophic factors (GDNF) family receptors α -1,2,3 and 4 combination are (refreshing derived from glial cell-line Through trophic factors, neurturin, artemin and persephin) one of combine after be activated (Plaza-Menacho, I., et al.,Trends Genet.,2006,22：627-636).Known RET skin and the incoming nociceptor of intestines development and Played an important role in survival.The mouse that RET kinases is knocked out lacks enteric nervous member, and with other nervous system abnormalities, shows Functional r ET kinase proteins product (Taraviras, S.et al., Development, 1999,126 are needed in growth course: 2785-2797).Moreover, to being characterized as due to a lack of obstruction of colon caused by Normal Colon weakening effect (enervation) Hirschsprung disease patient population research have higher proportion familial and sporadic functional r ET mutation forfeiture (Butler Tjaden N.,et al.,Transl.Res.,2013,162：1-15).
Similarly, abnormal RET kinase activities and Multiple Endocrine knurl (MEN 2A and 2B), familial medullary thyroid carcinoma (FMTC), papillary thyroid carcinoma (PTC) and Hirschsprung sick (HSCR) relevant (Borello, M., et al., Expert Opin.Ther.Targets,2013,17:403-419).MEN 2A are a kind of extracellular rich in Cysteine domains by RET Mutation causes cancer syndrome caused by dimerization (it causes the constitutively activated of tyrosine kinase activity) through disulfide bond (Wells Jr,S.,et al.,J.Clin.Endocrinol.Metab.,2013,98:3149-3164).With the mutation Individual may develop medullary thyroid carcinoma (MTC), parathyroid hyperplasia and pheochromocytoma.MEN 2B are due on RET Caused by Met918Thr mutation, that it changes the specificity of EGFR-TK.MEN 2B are similar with MEN 2A, but lack first shape Other gland hyperplasia, and also result in the ganglionic development of many mucous membranes of lip, tongue and enteron aisle.Connect promoter and NH2 ends Domain or with the incoherent gene in RET kinase c OOH ends so as to formed composition activation chimeric versions thereof acceptor (RET/ PTC chromosomal rearrangement) be considered as in PTC tumour firing event (Viglietto, G.et al., Oncogene, 1995, 11：1207-1210).PTC covers about the 80% of all thyroid cancers.These as shown by data, it is probably to be used to treat to suppress RET The pain related with other gastrointestinal disorders to IBS and there is attraction for treat the cancer with composition RET kinase activities The therapeutic strategy of power.
Invention summary
The present invention relates to the compound according to formula (I) or its pharmaceutically-acceptable salts:
Wherein：
X is N or CR5；
Y is key or-O-；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6；
R1For hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl or (C3-C6) cycloalkyl；
R2And R3It is each independently selected from hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl Base, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-with ((C1-C6) alkyl) ((C1-C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy Or (C3-C6) cycloalkyloxy is optionally by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy takes Generation；
R4For phenyl or 5- or 6- unit's heteroaryls, it is each optionally by one, two or three independently selected from following Substituent substitution：Halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, phenyl, 5- or 6- members Heteroaryl, hydroxyl ,-OR7、-CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl Base, (C1-C4) alkoxy, halo (C1-C4) alkoxy ,-NR8R9Or-CONR8R9Substitution；And wherein described 5- or 6- unit's heteroaryls Substituent is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
R5For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alcoxyl Base, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkyl) ((C1- C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3-C6) cycloalkyloxy times Selection of land is by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
Or R3And R5Carbon atom in connection be combined together expression 5- or 6- yuan of rings, optionally comprising one, two Individual or three hetero atoms independently selected from nitrogen, oxygen and sulphur, wherein the ring optionally by one or two under The substituent substitution stated：Halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alcoxyl Base, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino-and ((C1-C4) alkyl) ((C1- C4) alkyl) amino；
Each R6Independently selected from halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl Base, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-with ((C1-C6) alkyl) ((C1-C6) alkyl) amino-；
R7For (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or 4- be to 6- circle heterocycles alkyl；Wherein institute State (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；And its Described in (C3-C6) cycloalkyl optionally replaces by one or two independently selected from following substituents：(C1-C4) alkyl, halogen Generation (C1-C4) alkyl, hydroxyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy and halo (C1-C4) alkoxy；And wherein described 4- To 6- circle heterocycles alkyl optionally by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) alkyl substituent Substitution；With
R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, amino (C1-C4) alkyl-, ((C1-C4) alkyl) amino (C1-C4) alkyl-and ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C1-C4) alkyl-；
Or R8And R9Nitrogen in connection be combined together represent 5- or 6- member saturations ring, optionally containing selected from The other hetero atom of oxygen, nitrogen and sulphur, wherein the ring is optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl or hydroxyl Base (C1-C4) alkyl substitution；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- Phenylurea, 1- (5- (tert-butyl group) isoxazole -3-bases) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) Urea, 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ethylphenyls) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ((6- oxos -1,6- Dihydropyridine -3- bases) epoxide) phenyl) -3- (p- tolyl) urea, 1- (4- ((6- oxo -1,6- dihydropyridine -3- bases) oxygen Base) phenyl) -3- (3- (trifluoromethyl) phenyl) ureas or 1- (4- (tert-butyl group) phenyl) -3- (4- ((6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) epoxide) phenyl) urea.
The invention further relates to the compound including formula (I) and the pharmaceutical composition of pharmaceutically acceptable excipient.
The invention further relates to a kind of method for treating IBS, it includes effective dose is administered to people in need The compound or its pharmaceutically-acceptable salts of formula (I).The invention further relates to a kind of method for the treatment of cancer, it is included in need People administration effective dose formula (I) compound or its pharmaceutically-acceptable salts.
The invention further relates to formula (I) compound, for treating.The invention further relates to the compound of formula (I) or its pharmacy Upper acceptable salt is used for the purposes for treating IBS.The invention further relates to the compound of formula (I) or its can pharmaceutically connect It is used for the purposes for the treatment of cancer by salt.
The disease for being used for treating RET mediations is being prepared the invention further relates to the compound of formula (I) or its pharmaceutically-acceptable salts Purposes in the medicine of disease.Prepared the invention further relates to the compound of formula (I) or its pharmaceutically-acceptable salts for treating intestines Purposes in the medicine of irritable syndrome.Use is being prepared the invention further relates to the compound of formula (I) or its pharmaceutically-acceptable salts Purposes in the medicine for the treatment of cancer.
Brief description
Fig. 1 shows the X-ray powder diffraction figure case of compound A free alkali anhydrides.
Fig. 2 shows the Raman spectrum of the hydrate 1 of compound A free alkali anhydrides.
Fig. 3 shows the differential scanning calorimetry trace of compound A free alkali anhydrides.
Fig. 4 shows the thermogravimetry trace of compound A free alkali anhydrides.
Fig. 5 shows the X-ray powder diffraction figure case of compound A free alkalis hydrate 1.
Fig. 6 shows the Raman spectrum of compound A free alkalis hydrate 1.
Fig. 7 shows the differential scanning calorimetry trace of compound A free alkalis hydrate 1.
Fig. 8 shows the thermogravimetry trace of compound A free alkalis hydrate 1.
Fig. 9 shows the X-ray powder diffraction figure case of compound A free alkalis hydrate 2.
Figure 10 shows the Raman spectrum of compound A free alkalis hydrate 2.
Figure 11 shows the differential scanning calorimetry trace of compound A free alkalis hydrate 2.
Figure 12 shows the thermogravimetry trace of compound A free alkalis hydrate 2.
Figure 13 shows the X-ray powder diffraction figure case of compound A free alkalis hydrate 3.
Figure 14 shows the Raman spectrum of compound A free alkalis hydrate 3.
Figure 15 shows the differential scanning calorimetry trace of compound A free alkalis hydrate 3.
Figure 16 shows the thermogravimetry trace of compound A free alkalis hydrate 3.
Figure 17 shows the X-ray powder diffraction figure case of compound A free alkalis hydrate 4.
Figure 18 shows the Raman spectrum of compound A free alkalis hydrate 4.
Figure 19 shows the differential scanning calorimetry trace of compound A free alkalis hydrate 4.
Figure 20 shows the thermogravimetry trace of compound A free alkalis hydrate 4.
Figure 21 shows the X-ray powder diffraction figure case of compound A free alkalis hydrate 5.
Figure 22 shows the Raman spectrum of compound A free alkalis hydrate 5.
Figure 23 shows the differential scanning calorimetry trace of compound A free alkalis hydrate 5.
Figure 24 shows the thermogravimetry trace of compound A free alkalis hydrate 5.
Figure 25 shows the X-ray powder diffraction figure case of compound A hydrochloride anhydrides.
Figure 26 shows the Raman spectrum of compound A hydrochloride anhydrides.
Figure 27 shows the differential scanning calorimetry trace of compound A hydrochloride anhydrides.
Figure 28 shows the thermogravimetry trace of compound A hydrochloride anhydrides.
Figure 29 shows the X-ray powder diffraction figure case of compound A hydrochloride hydrates.
Figure 30 shows the Raman spectrum of compound A hydrochloride hydrates.
Figure 31 shows the differential scanning calorimetry trace of compound A hydrochloride hydrates.
Figure 32 shows the thermogravimetry trace of compound A hydrochloride hydrates.
Figure 33 shows the X-ray powder diffraction figure case of compound A esilates.
Figure 34 shows the Raman spectrum of compound A esilates.
Figure 35 shows the differential scanning calorimetry trace of compound A esilates.
Figure 36 shows the thermogravimetry trace of compound A esilates.
Figure 37 shows the X-ray powder diffraction figure case of compound A sulfate.
Figure 38 shows the Raman spectrum of compound A sulfate.
Figure 39 shows the differential scanning calorimetry trace of compound A sulfate.
Figure 40 shows the thermogravimetry trace of compound A sulfate.
Detailed description of the invention
The present invention relates to the compound of formula as defined above (I) or its pharmaceutically-acceptable salts.The invention further relates to The compound or its pharmaceutically-acceptable salts of formula (I), wherein:
X is N or CR5；
Y is key or-O-；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6；
R1For hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl or (C3-C6) cycloalkyl；
R2And R3It is each independently selected from hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl Base, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-with ((C1-C6) alkyl) ((C1-C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy Or (C3-C6) cycloalkyloxy is optionally by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy takes Generation；
R4For phenyl or 5- or 6- unit's heteroaryls, it is each optionally by one, two or three independently selected from following Substituent substitution：Halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, phenyl, 5- or 6- members Heteroaryl, hydroxyl ,-OR7、-CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl Base, (C1-C4) alkoxy, halo (C1-C4) alkoxy ,-NR8R9Or-CONR8R9Substitution；And wherein described 5- or 6-- members heteroaryl Base substituent is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
R5For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alcoxyl Base, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkyl) ((C1- C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3-C6) cycloalkyloxy times Selection of land is by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
Or R3And R5Carbon atom in connection be combined together expression 5- or 6- yuan of rings, optionally comprising one, two Individual or three hetero atoms independently selected from nitrogen, oxygen and sulphur, wherein the ring optionally by one or two under The substituent substitution stated：Halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alcoxyl Base, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino-and ((C1-C4) alkyl) ((C1- C4) alkyl) amino；
Each R6Independently selected from halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl Base, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-with ((C1-C6) alkyl) ((C1-C6) alkyl) amino-；
R7For (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or 4- be to 6- circle heterocycles alkyl；Wherein institute State (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；And its Described in (C3-C6) cycloalkyl optionally replaces by one or two independently selected from following substituents：(C1-C4) alkyl, halogen Generation (C1-C4) alkyl, hydroxyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy and halo (C1-C4) alkoxy；Wherein described 4- To 6- circle heterocycles alkyl optionally by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) alkyl substituent Substitution；With
R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl and halogen (C1-C4) alkyl；
Or R8And R9Nitrogen in connection be combined together represent 5- or 6- member saturations ring, optionally containing selected from The other hetero atom of oxygen, nitrogen and sulphur, wherein the ring is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl takes Generation；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- Phenylurea, 1- (5- (tert-butyl group) isoxazole -3-bases) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) Urea, 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ethylphenyls) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ((6- oxos -1,6- Dihydropyridine -3- bases) epoxide) phenyl) -3- (p- tolyl) urea, 1- (4- ((6- oxo -1,6- dihydropyridine -3- bases) oxygen Base) phenyl) -3- (3- (trifluoromethyl) phenyl) ureas or 1- (4- (tert-butyl group) phenyl) -3- (4- ((6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) epoxide) phenyl) urea.
The invention further relates to the compound of formula (II) or its pharmaceutically-acceptable salts:
Wherein X, Z1、Z2、Z3、Z4、R2、R3And R4Defined according to formula (I), condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- phenylureas.
The invention further relates to the compound of formula (III) or its pharmaceutically-acceptable salts:
Wherein X, Z1、Z2、Z3、Z4、R2、R3And R4Defined according to formula (I), condition is that the compound is not 1- (5- (tert-butyl group) isoxazole -3-bases) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (the chloro- 3- of 4- (trifluoromethyl) phenyl) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ethylphenyls) - 3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ((6- oxo -1,6- dihydropyridine -3- bases) Epoxide) phenyl) -3- (p- tolyl) urea, 1- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (3- (trifluoromethyl) phenyl) urea or 1- (4- (tert-butyl group) phenyl) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) benzene Base) urea.
The invention further relates to the compound of formula (IV) or its pharmaceutically-acceptable salts:
Wherein Z1、Z2、Z3、Z4、R2、R3、R4And R5Defined according to formula (I), condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- phenylureas.
The invention further relates to the compound of formula (V) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I).
The invention further relates to the compound of formula (VI) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4And R5Defined according to formula (I), condition is that the compound is not 1- (4- (5- hydroxyls -1- Oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- phenylureas.
The invention further relates to the compound of formula (VII) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I).
The invention further relates to the compound of formula (VIII) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I).
The invention further relates to the compound of formula (IX) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I).
The invention further relates to the compound of formula (X) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I).
The invention further relates to the compound of formula (XI) or its pharmaceutically-acceptable salts:
Wherein X, Z1、Z2、Z3、Z4、R2And R3Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- Phenylurea；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XII) or its pharmaceutically-acceptable salts:
Wherein Z1、Z2、Z3、Z4、R2、R3And R5Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- Phenylurea；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XIII) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XIV) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- Phenylurea；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XV) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XVI) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XVII) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XVIII) or its pharmaceutically-acceptable salts:
Wherein R2、R3、R4、R5And R6Defined according to formula (I), and wherein：
A is N or CR13；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- member heteroaryls Base, hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halogen Generation (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are appointed Selection of land is by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
And condition is when A is CR13When, R10、R11、R12And R13In at least one be hydrogen.
The invention further relates to the compound of formula (XIX) or its pharmaceutically-acceptable salts:
Wherein Z1、Z2、Z3、Z4、R2、R3And R5Defined according to formula (I), and wherein：
A1、A2And A3One of be selected from O, S and NR15, and other two is each independently selected from N and CH；
R14For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl ,-OR7、- CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；With
R15For hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or phenyl.
In another embodiment, X is CR5.In one particular embodiment, X is N.
In one particular embodiment, Y is key.In another particular, Y is-O-.
In another embodiment, Z1、Z2、Z3And Z4It is each independently N, CH or CR6, wherein Z1、Z2、Z3And Z4In 0th, 1,2 or 3 are N, and Z1、Z2、Z3And Z4In 0,1,2 or 3 be CR6.In another embodiment, Z1、Z2、Z3And Z4Respectively From independently being N, CH or CR6, wherein Z1、Z2、Z3And Z4In 0,1 or 2 be N, and Z1、Z2、Z3And Z4In 0,1 or 2 be CR6。 In another embodiment, Z1、Z2、Z3And Z4It is each independently CH or CR6.In one particular embodiment, Z1、Z2、Z3 And Z4It is each independently CH.In another embodiment, Z1、Z2、Z3And Z4One of be CR6, and other three respective independences Ground is CH.In another embodiment, Z2For CR6And Z1、Z3And Z4It is each independently CH.In another embodiment, Z1For CR6And Z2、Z3And Z4It is each independently CH.In another embodiment, Z1、Z2、Z3And Z4In two independently of one another For CR6, and other two is each independently CH.In another embodiment, Z1And Z2It is each independently CR6, and Z3With Z4It is each independently CH.In another embodiment, Z2And Z3It is each independently CR6, and Z1And Z4It is each independently CH。
In another embodiment, Z1、Z2、Z3And Z4One of be N, and its excess-three is each independently CH or CR6. In one particular, Z1、Z2、Z3And Z4One of be N, and its excess-three is each independently CH.In another embodiment party In case, Z1For N, and Z2、Z3And Z4It is each independently CH or CR6.In another embodiment, Z1For N, Z2For CR6, and Z3 And Z4It is each independently CH.In another embodiment, Z2For N, and Z1、Z3And Z4It is each independently CH or CR6.Another In one embodiment, Z2For N, Z1For CR6, and Z3And Z4It is each independently CH.In another embodiment, Z1、Z2、Z3 And Z4In two be N, and other two is each independently CH or CR6.In another embodiment, Z1、Z2、Z3And Z4In two Individual is N, and other two is each independently CH.In another embodiment, Z1And Z4For N, and Z2And Z3Independently of one another For CH or CR6.In another embodiment, Z1And Z4For N, and Z2And Z3It is each independently CR6.In another embodiment In, Z1And Z4For N, Z2For CR6, and Z3For CH.In another embodiment, Z1And Z3For N, and Z2And Z4It is each independently CH or CR6.In another embodiment, Z1And Z3For N, and Z2And Z4It is each independently CR6.In another embodiment In, Z1And Z3For N, Z2For CR6, and Z4For CH.
In another embodiment, R1For hydrogen or (C1-C4) alkyl.In one particular embodiment, R1For hydrogen, first Base or ethyl.In a further particular, R1For hydrogen.
In another embodiment, R2For hydrogen, fluorine, chlorine, (C1-C4) alkyl, halo (C1-C4) alkyl, hydroxyl, (C1- C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkane Base) ((C1-C6) alkyl) amino-.In another embodiment, R2For hydrogen, (C1-C4) alkyl or (C1-C4) alkoxy.One In individual particular, R2For hydrogen, methyl, ethyl, methoxy or ethoxy.In a further particular In, R2For hydrogen.
In another embodiment, R3For hydrogen, fluorine, chlorine, (C1-C4) alkyl, halo (C1-C4) alkyl, hydroxyl, (C1- C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkane Base) ((C1-C6) alkyl) amino-.In another embodiment, R3For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkanes Epoxide.In one particular embodiment, R3For hydrogen, fluorine, methyl, hydroxyl, methoxyl group, difluoro-methoxy, ethyoxyl, positive third oxygen Base, isopropoxy, 3- fluorine propoxyl group, ring propoxyl group or methylamino-.In another embodiment, R3For hydrogen or (C1-C4) Alkoxy.In another particular, R3For hydrogen or ethyoxyl.In a further particular, R3For Ethyoxyl.In another further particular, R3For hydrogen.
In another embodiment, R4For phenyl, it is optionally by one, two or three independently selected from following Substituent replaces：Halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, phenyl, 5- or 6- members be miscellaneous Aryl, hydroxyl ,-OR7、-CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy ,-NR8R9Or-CONR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls take Dai Ji is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution.In another embodiment, R4For phenyl, It is optionally replaced by one, two or three independently selected from following substituents：Fluorine, chlorine, (C1-C6) alkyl, halo (C1- C4) alkyl, cyano group, (C1-C4) alkoxy, hydroxyl (C2-C4) alkoxy-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alkoxy-, ((C1-C4) alkyl) amino (C2-C4) alkoxy-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2- C4) alkoxy -, (3- methy oxetane -3- bases) epoxide-and-CONH2；Wherein described (C1-C6) alkyl is optionally by cyanogen Base, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkyl) amino-or ((C1-C4) alkyl) ((C1-C4) alkyl) amino takes Generation.In another embodiment, R4For phenyl, it is optionally by one or two independently selected from (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxy and (3- methy oxetane -3- bases) epoxide-substituent substitution；It is wherein described (C1-C4) alkyl is optionally by cyano group, hydroxyl or dimethylamino-substitution.In another embodiment, R4For phenyl, its Selection of land is by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) alkyl substituent substitution；Wherein described (C1- C4) alkyl is optionally by cyano group, hydroxyl or dimethylamino-substitution.
In another embodiment, R4For furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazolium It is Ji, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl, phonetic Piperidinyl or triazine radical, it is each optionally replaced by one, two or three independently selected from following substituents：Halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, phenyl, 5- or 6- unit's heteroaryls, hydroxyl ,-OR7、- CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy ,-NR8R9Or-CONR8R9Substitution；Wherein described 5- or 6- unit's heteroaryls substituent optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution.In another embodiment, R4For furyl, thienyl, pyrrole radicals, miaow Oxazolyl, pyrazolyl, triazolyl, tetrazole radical, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group, Pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or triazine radical, it is each optionally by one, two or three under The substituent substitution stated：Fluorine, chlorine, (C1-C6) alkyl, halo (C1-C4) alkyl, cyano group, (C1-C4) alkoxy, hydroxyl (C2-C4) Alkoxy-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alkoxy-, ((C1-C4) alkyl) amino (C2-C4) Alkoxy-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2-C4) alkoxy-and-CONH2；Wherein described (C1-C6) alkyl Optionally by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkyl) amino-or ((C1-C4) alkyl) ((C1-C4) alkane Base) amino substitution.
In another embodiment, R4For pyridine radicals, it is optionally by one, two or three independently selected from following Substituent substitution：Fluorine, chlorine, (C1-C6) alkyl, halo (C1-C4) alkyl, cyano group, (C1-C4) alkoxy, hydroxyl (C2-C4) alkane Epoxide-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alkoxy-, ((C1-C4) alkyl) amino (C2-C4) alkane Epoxide-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2-C4) alkoxy-and-CONH2；Wherein described (C1-C6) alkyl times Selection of land is by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkyl) amino-or ((C1-C4) alkyl) ((C1-C4) alkane Base) amino substitution.In another embodiment, R4For pyridine radicals, it is optionally by one or two independently selected from (C1- C4) alkyl and halo (C1-C4) alkyl substituent substitution；Wherein described (C1-C4) alkyl is optionally by cyano group, hydroxyl or diformazan Base amino-substitution.
In another embodiment, R4For furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazolium It is Ji, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl, phonetic Piperidinyl or triazine radical, it is each optionally by one or two independently selected from (C1-C4) alkyl and halogen (C1-C4) alkyl Substituent replaces.In another embodiment, R4Wei isoxazolyls, it is optionally by (C1-C4) alkyl or halo (C1-C4) alkane Base replaces.
In another embodiment, R5For hydrogen, fluorine, chlorine, (C1-C4) alkyl, halo (C1-C4) alkyl, hydroxyl, (C1- C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkane Base) ((C1-C6) alkyl) amino-.In another embodiment, R5For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkanes Epoxide.In one particular embodiment, R5For hydrogen, fluorine, methyl, hydroxyl, methoxyl group, difluoro-methoxy, ethyoxyl, positive third oxygen Base, isopropoxy, 3- fluorine propoxyl group, ring propoxyl group or methylamino-.In another embodiment, R5For hydrogen or (C1-C4) Alkoxy.In another particular, R5For hydrogen or ethyoxyl.In a further particular, R5For Ethyoxyl.In another further particular, R5For hydrogen.
In another embodiment, R3And R5Carbon atom in connection is combined together expression 5- or 6- yuan of rings, appoints Selection of land includes hetero atom of the one, two or three independently selected from nitrogen, oxygen and sulphur, wherein the ring is optionally by one or two It is individual to replace independently selected from following substituents：Halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl Base, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino and ((C1- C4) alkyl) ((C1-C4) alkyl) amino.In another embodiment, R3And R5Carbon atom in connection represents benzene together Basic ring, it is optionally replaced by one or two independently selected from following substituents：Halogen, (C1-C4) alkyl, halo (C1- C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino and ((C1-C4) alkyl) ((C1-C4) alkyl) amino.In one particular embodiment, R3And R5With The carbon atom that they are connected represents benzyl ring together.
In another embodiment, R3And R5Carbon atom in connection represents pyridine radicals, pyridazinyl, pyrazine together Base, pyrimidine radicals or triazine radical, it is each optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, Hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino or ((C1-C4) alkyl) ((C1-C4) alkyl) amino substitution.In one particular embodiment, R3And R5Carbon in connection is former Son represents pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or triazine radical together.In a further particular, R3 And R5Carbon atom in connection represents pyridine radicals together.
In another embodiment, R3And R5Carbon atom in connection represent together furyl, dihydrofuran base, Thienyl, pyrrole radicals, pyrrolinyl, imidazole radicals, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, oxazolyls, thiazolyl, Isoxazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl group, wherein the furyl, dihydrofuran base, thienyl, pyrrole radicals, Pyrrolinyl, imidazole radicals, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, oxazolyls, thiazolyl, isoxazolyls or different thiophene Oxazolyl is optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alkoxy, halogen Generation (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino or ((C1-C4) alkyl) ((C1-C4) alkane Base) amino substitution.In one particular embodiment, R3And R5Carbon atom in connection represents furyl, dihydro furan together Mutter base, thienyl, pyrrole radicals, pyrrolinyl, imidazole radicals, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, oxazolyls, thiophene Oxazolyl, isoxazolyls, isothiazolyl, oxadiazolyls or thiadiazolyl group.In another particular, R3And R5With them The carbon atom of connection represents furyl, dihydrofuran base or pyrazolyl together.In another particular, R3And R5With The carbon atom that they are connected represents cyclopentenyl together.
In another embodiment, each R6Independently selected from halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino-and ((C1-C4) alkyl) ((C1-C6) alkyl) amino-.In one particular embodiment, each R6 Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, cyclopropyl, methoxyl group, isopropoxy and dimethylamino-.At one In further particular, R6For fluorine.In another further particular, R6For methyl.
In another embodiment, R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, Amino (C1-C4) alkyl-, ((C1-C4) alkyl) amino (C1-C4) alkyl and ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C1- C4) alkyl.In another embodiment, R8And R9Nitrogen in connection is combined together the ring for representing 5- or 6- member saturations, Optionally contain the other hetero atom selected from oxygen, nitrogen and sulphur, wherein the ring is optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl or hydroxyl (C1-C4) alkyl substitution.
In another embodiment, R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl and halo (C1-C4) alkyl； Or R8And R9Nitrogen in connection is combined together the ring for representing 5- or 6- member saturations, optionally containing selected from oxygen, nitrogen and sulphur Other hetero atom, wherein the ring is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution.At another In embodiment, R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl and halo (C1-C4) alkyl.In another embodiment In, R8And R9Nitrogen in connection is combined together the ring for representing 5- or 6- member saturations, optionally containing selected from oxygen, nitrogen and sulphur Other hetero atom, wherein the ring is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution.
In another embodiment, A is CR13, and R13For hydrogen, halogen, halo (C1-C4) alkyl, furyl, thiophene Base, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazoles Base, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or triazine radical, wherein the furyl, thienyl, pyrrole radicals, Imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazoles Base, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or triazine radical are optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkane Base replaces.In another embodiment, A is CR13, and R13For hydrogen, fluorine, chlorine or trifluoromethyl.In a particular In, A is CH.In another particular, A is N.
In another embodiment, R10For hydrogen or halogen.In one particular embodiment, R10For hydrogen or fluorine.One In individual further embodiment, R10For hydrogen.
In another embodiment, R11For hydrogen, fluorine, chlorine, (C1-C6) alkyl, halo (C1-C4) alkyl, cyano group, (C1- C4) alkoxy, hydroxyl (C2-C4) alkoxy-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alkoxy-, ((C1-C4) alkyl) amino (C2-C4) alkoxy-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2-C4) alkoxy-, (3- Methy oxetane -3- bases) epoxide-or-CONH2；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) Alkoxy, amino, ((C1-C4) alkyl) amino or ((C1-C4) alkyl) ((C1-C4) alkyl) amino substitution.In another implementation In scheme, R11For hydrogen, (C1-C4) alkoxy or (C1-C6) alkyl；Wherein described (C1-C6) alkyl optionally by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkyl) amino or ((C1-C4) alkyl) ((C1-C4) alkyl) amino substitution.Another In individual embodiment, R11For (C1-C4) alkyl, it is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkane Base) amino or ((C1-C4) alkyl) ((C1-C4) alkyl) amino substitution.
In another embodiment, R12For halo (C1-C4) alkyl.In one particular embodiment, R12For trifluoro Methyl.
In another embodiment, A1For CH, A2For O, and A3For N；Or A1For CH, A2For N, and A3For O；Or A1For CH, A2For N, and A3For NR15.In another embodiment, A1For CH, A2For O, and A3For N.In another embodiment, A1For CH, A2For N, and A3For O.In another embodiment, A1For CH, A2For N, and A3For NR15。
In another embodiment, R14For hydrogen, halogen, (C1-C4) alkyl, halo (C1-C4) alkyl or (C3-C6) cycloalkanes Base.In another embodiment, R14For (C1-C4) alkyl or halo (C1-C4) alkyl.In another embodiment, R14For Halo (C1-C4) alkyl.
In another embodiment, R15For hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl or benzene Base.In one particular embodiment, R15For hydrogen, methyl, ethyl or phenyl.
In one particular embodiment, the present invention relates to the compound of formula (I) or its pharmaceutically-acceptable salts, wherein：
X is CR5；
Y is key；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6, wherein Z1、Z2、Z3And Z4In 0,1 or 2 be N and Z1、Z2、Z3 And Z4In 0,1 or 2 be CR6；
R1For hydrogen；
R2For hydrogen, (C1-C4) alkyl or (C1-C4) alkoxy；
R3For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；
R4For phenyl, it is optionally replaced by one, two or three independently selected from following substituents：Fluorine, chlorine, (C1-C6) alkyl, halo (C1-C4) alkyl, cyano group, (C1-C4) alkoxy, hydroxyl (C2-C4) alkoxy-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alkoxy-, ((C1-C4) alkyl) amino (C2-C4) alkoxy-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2-C4) alkoxy -, (3- methy oxetane -3- bases) epoxide-and-CONH2；It is wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkyl) amino-or ((C1-C4) alkane Base) ((C1-C4) alkyl) amino-substitution；
R5For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；With
Each R6Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, cyclopropyl, methoxyl group, isopropoxy and diformazan Base amino-.
In another particular, the present invention relates to the compound of formula (I) or its pharmaceutically-acceptable salts, its In：
X is CR5；
Y is key；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6, wherein Z1、Z2、Z3And Z4In 0,1 or 2 be N and Z1、Z2、Z3 And Z4In 0,1 or 2 be CR6；
R1For hydrogen；
R2For hydrogen, (C1-C4) alkyl or (C1-C4) alkoxy；
R3For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；
R4For furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyls, thiazolyl, different Oxazolyl, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or triazine radical, its is each Optionally by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) alkyl substituent substitution；
R5For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；With
Each R6Independently selected from fluorine, chlorine, methyl, ethyl, difluoromethyl, cyclopropyl, methoxyl group, isopropoxy and diformazan Base amino-.
In another particular, the present invention relates to the compound of formula (XII) or its pharmaceutically-acceptable salts, its In：
Z1、Z2、Z3And Z4It is each independently N, CH or CR6, wherein Z1、Z2、Z3And Z4In 0,1 or 2 be N, and Z1、Z2、 Z3And Z4In 0,1 or 2 be CR6；
R2For hydrogen, (C1-C4) alkyl or (C1-C4) alkoxy；
R3For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；
R5For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；
A is N or CR13；
R10For hydrogen or halogen；
R11For hydrogen, fluorine, chlorine, (C1-C6) alkyl, halo (C1-C4) alkyl, cyano group, (C1-C4) alkoxy, hydroxyl (C2-C4) Alkoxy-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alkoxy-, ((C1-C4) alkyl) amino (C2-C4) Alkoxy-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2-C4) alkoxy -, (3- methy oxetane -3- bases) oxygen Base-or-CONH2；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkane Base) amino or ((C1-C4) alkyl) ((C1-C4) alkyl) amino substitution；
R12For halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl, furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazole Base, tetrazole radical, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrrole Piperazine base, pyrimidine radicals or triazine radical, wherein the furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, Oxazolyl, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals Or triazine radical is optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution.
In another particular, the present invention relates to the compound of formula (XIX) or its pharmaceutically-acceptable salts, its In：
Z1、Z2、Z3And Z4It is each independently N, CH or CR6, wherein Z1、Z2、Z3And Z4In 0,1 or 2 be N, and Z1、Z2、 Z3And Z4In 0,1 or 2 be CR6；
R2For hydrogen, (C1-C4) alkyl or (C1-C4) alkoxy；
R3For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；
R5For hydrogen, hydroxyl, (C1-C4) alkoxy or (C3-C6) cycloalkyloxy；
A1For CH, A2For O and A3For N；Or A1For CH, A2For N, and A3For O；Or A1For CH, A2For N, and A3For NR15；
R14For (C1-C4) alkyl or halo (C1-C4) alkyl；With
R15For hydrogen, methyl, ethyl or phenyl.
The invention further relates to the compound in test portion example.
The specific compound of the present invention includes：
1- (the fluoro- 4- of 2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (3- (4- methyl isophthalic acid H- miaows Azoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (1- oxo -2,5,6,7- tetrahydrochysene -1H- rings penta Diene simultaneously [c] pyridin-4-yl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydro-1 h-pyrazoles simultaneously [4,3-c] pyridin-7-yl) phenyl) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- isopropyls Epoxide -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- bis- Hydrogen-[2,3'- bipyridyls] -5- bases) urea；
1- (the fluoro- 4- of 2- (5- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- rings Butane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -2- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- isopropyls Epoxide -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyls Base -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- hydroxyls Base ethyl) -3- (trifluoromethyl) phenyl) urea；
((1,1,1- tri- is fluoro- by 5- by -3- by 1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) 2- methylpropane -2- base) isoxazole -3-bases) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- first Base oxetanes -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- first Base oxetanes -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1, The fluoro- 2- methylpropanes -2- bases of 1- tri-) isoxazole -3-base) urea；
1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (5- (1,1, The fluoro- 2- methylpropanes -2- bases of 1- tri-) isoxazole -3-base) urea；
1- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- (piperazine -1- ylmethyls) -3- (fluoroforms Base) phenyl) urea；
1- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ring propoxyl group -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- methoxyl group -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- oxo -2,3,4,5- tetrahydrofurans [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxyls Base propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxyls Base propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (2- (difluoromethyl) -4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((4- Ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((4- ethyl piperazines Piperazine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- second Base piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (4- ethyoxyl -2- oxo -1,2- dihydro-pyrimidin -5- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 5-) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 4-) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoros Methyl) phenyl) urea；
1- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) -3- (4- methyl -2- (7- oxo -6, 7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) pyrimidine -5- bases) urea；
1- (the fluoro- 4- of 2- (2- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- rings Butane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyls Base -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoros Methyl) phenyl) urea；
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) - 4- methylpyrimidine -5- bases) urea；
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) - 4- methylpyrimidine -5- bases) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (morpholinomethyl) - 3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1, The fluoro- 2- methylpropanes -2- bases of 1- tri-) isoxazole -3-base) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyls Base -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyls Base -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxyls Base propane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- first Base -1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- Methylpyrimidine -5- bases) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- ethyl-pyrimidine -5- bases) -3- (3- (4- first Base -1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- first Base -1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) urea；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- Methylpyrimidine -5- bases) urea；
2- (4- (3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) - 2- (trifluoromethyl) phenyl) -2- methyl propanamides；
1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
2- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) - 2- (trifluoromethyl) phenyl) -2- methyl propanamides；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- hydroxyls -2,2- Dimethyl propyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1,6- dihydros Pyridin-3-yl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxyls Ylmethyl) cyclopropyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (5- first Base -1,3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea；
1- (3- (tert-butyl group) -1- phenyl -1H- pyrazoles -5- bases) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) benzene Base) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((4- ethyl piperazidines - 1- yls) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxyls Base propane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethoxies Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (the fluoro- 4- of 2- (1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- (hydroxymethyl) Cyclopropyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (fluoro- 5- (fluoroforms of 2- Base) phenyl) urea；
1- (4- (t-butoxy) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -2- fluorophenyls) urea；
1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea；
1- (4- ((2- dicyanopropane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- hydroxyl -1- first Basic ring butoxy) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- isopropyls -3- Methylpyrrolidin- 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (fluoro- 5- (fluoroforms of 2- Base) phenyl) urea；
1- (chloro- 5'- ethyoxyls -6'- oxos -1', the 6'- dihydros of 6--[2,3'- bipyridyls] -5- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxyls Ylmethyl) cyclopropyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (6- (2- hydroxy propanes - 2- yls) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2,6- difluorophenyls) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- Methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (6- isopropoxies -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (3- (difluoromethyl) -4- ((3- methy oxetane -3- bases) epoxide) phenyl) -3- (4- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (the fluoro- 4- of 2- (5- hydroxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- rings Butane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (5- (methylamino) -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
((4- oxo -4,5- dihydrofuran is simultaneously [3,2-c] by the fluoro- 4- of 2- by 1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- Pyridin-7-yl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (2- Quinoline is for ethyoxyl) -5- (trifluoromethyl) phenyl) urea；
1- (5'- methoxyl group -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (6- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) pyridin-3-yl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6- ethyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (fluoro- 6'- oxos -1', the 6'- dihydros of 5'- ethyoxyls -5--[3,3'- bipyridyls] -6- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (6- cyclopropyl -5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- fluoro- 3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (5- (3- fluorine propoxyl group) -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) phenyl) urea；
1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (azetidine -1- ylmethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (5'- ethyoxyl -6- methoxyl group -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (pyrroles Alkane -1- ylmethyls) -3- (trifluoromethyl) phenyl) urea；
1- (6- (dimethylamino) -5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (4- (1- ethyl -6- oxo -1,6- dihydropyridine -3- bases) - 2- fluorophenyls) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (5- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -3- methylpyrazine -2- bases) urea；
1- (5'- ethyoxyl -6- isopropoxy -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- hydroxyethyls) - 3- (trifluoromethyl) phenyl) urea；
1- (4- ((1,3- dimethyl azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethoxies Base -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- hydroxyl -2- first Base propane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2,3- difluorophenyls) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- hydroxyl -2- first Base propane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (5- (3- fluorine propoxyl group) -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- isopropyl oxygen Base -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- hydroxy propanes - 2- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- (hydroxymethyl) Ring propoxyl group) -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- ((3- methy oxetane -3- bases) epoxide) phenyl) -3- (4- (4- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (the fluoro- 3- hydroxypropyls of 2,2- bis-) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (4- (difluoro-methoxy) -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (fluoro- 5- (fluoroforms of 2- Base) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- hydroxy propanes - 2- yls) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxos -5- Propoxyl group -1,6- dihydropyridine -3- bases) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (hydroxymethyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- (hydroxymethyl) Cyclobutoxy group) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -2- fluorophenyls) urea；
1- (the fluoro- 4- of 2- (5- isopropoxy -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- methyl -4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (6- oxo -5- propoxyl group -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((fluoro- 2- methyl of 1- Propane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (2- hydroxyl -5- (trifluoros Methyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- '-hydroxyethoxies Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((1,3- dimethyl pyrrolidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (oxygen of 2- hydroxyls third Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- methyl isophthalic acids H- Pyrazoles -4- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes -3- Base) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (6- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- methyl ring fourth oxygen Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl isophthalic acids, 1- Sulfur dioxide azetidine (dioxidothietan) -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (ethoxyl methyl) - 3- (trifluoromethyl) phenyl) urea；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- Fluorophenyl) urea；
1- (2- ethyoxyls -4- fluoro- 5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -2- fluorophenyls) urea；
(S) -1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- fluorine pyrroles Cough up alkane -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (the fluoro- 5- (three of 2- Methyl fluoride) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (fluoro- 3- (fluoroforms of 4- Base) phenyl) urea；
1- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1, 6- dihydropyridine -3- bases) phenyl) urea；
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) - 2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- methoxyl groups -2- Methylpropane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -3- fluorophenyls) urea；
1- (4- (3,3- difluoros cyclobutoxy group) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -2- fluorophenyls) urea；
4- (3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea groups) -2- (fluoroforms Base) benzamide；
1- (4- isopropoxies -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) Urea；
1- (4- (5- (difluoro-methoxy) -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- hydroxyls Ethyoxyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (2- fluoro- 4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl tetrahydrochysenes Furans -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- rings Butane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- ((3- methy oxetane -3- bases) epoxide) phenyl) -3- (4- (6- oxo -1, 6- dihydropyridine -3- bases) phenyl) urea；
1- (3,4- dichlorophenyls) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) Urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea；
1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- (2- hydroxyl second Epoxide) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- (2- hydroxyl-oxethyls) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- Methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzsulfamide；
1- (4- (1- amino-ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (1- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- (pyrroles Cough up alkane -1- bases) ethyl) -3- (trifluoromethyl) phenyl) urea；
1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) pyrimidine -5- bases) urea；
((1,1,1- tri- is fluoro- by 5- by -3- by 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) 2- methylpropane -2- base) isoxazole -3-bases) urea；
((1,1,1- tri- is fluoro- by 5- by -3- by 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) 2- methylpropane -2- base) isoxazole -3-bases) urea；
1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (4- (2- methoxyl groups Ethyoxyl) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidines - 1- yls) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl)-phenyl) -3- (2- (5- (2- methoxies Base oxethyl) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (4- (2- methoxy ethoxies) -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide；
1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases)-phonetic Pyridine -5- bases) urea groups) -5- (trifluoromethyl) benzamide；
1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；With
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- second Base piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea；
Or its pharmaceutically-acceptable salts.
Those skilled in the art recognize that when using different name softwares, the compounds of this invention can have different names Claim.
The invention further relates to formula (I)-(XIX) compound or the compound of any example its pharmaceutically-acceptable salts, For treating, the treatment that wherein subject is the mankind is particularly used for.Especially, for treating the disease: intestines that following RET are mediated Irritable syndrome (IBS), including diarrhea predominance type, constipation leading type or alternating bowel movement pattern, feature aerogastria, feature are just Secret, functional diarrhea, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, feature oesophagus Disease, feature Depressed rats, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, Hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid carcinoma, undifferentiated thyroid carcinoma, papillary thyroid Cancer, brain tumor, cavum peritoneale cancer, solid tumor, other lung cancer, head and neck cancer, glioma, neuroblastoma, Von Hipple- Lindau syndromes and kidney neoplasms, breast cancer, carcinoma of fallopian tube, oophoroma, transitional-cell carinoma, prostate cancer, esophagus and oesophagus Cancer, cancer of bile ducts and the gland cancer of stomach junction.Especially, the present invention relates to formula (I)-(XIX) compound or any example Compound or its pharmaceutically-acceptable salts, for treating following diseases: IBS (IBS), including diarrhea predominance type, Constipation leading type or alternating bowel movement pattern, feature aerogastria, functional consitipation, functional diarrhea, non-specific feature intestines Disease, functional abdominal pain syndrome, chronic idiopathic constipation, Functional Esophageal Disorders, feature Depressed rats, feature anus Rectal pain, inflammatory bowel disease, non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicularis thyroid gland Cancer, undifferentiated thyroid carcinoma, papillary thyroid carcinoma, brain tumor, cavum peritoneale cancer, solid tumor, other lung cancer, head and neck cancer, neuroglia Matter knurl, neuroblastoma, Von Hipple-Lindau syndromes and kidney neoplasms, breast cancer, carcinoma of fallopian tube, oophoroma, transition Cancer, cancer of bile ducts and gland cancer at type cell cancer, prostate cancer, esophagus and Esophagogastric junction.
The invention further relates to the compound of the formula as medicine (I)-(XIX) compound or any example its pharmaceutically Acceptable salt.In another embodiment, the disease for treating RET mediations is being prepared the present invention relates to the compound of the present invention Purposes in the medicine of disease.The invention further relates to formula (I)-(XIX) compound or the compound or its pharmacy of any example Upper acceptable salt, prepares the medicine for treating IBS.The invention further relates to formula (I)-(XIX) compound or appoint A kind of its pharmaceutically-acceptable salts of the compound of example, prepare the medicine for treating cancer.
The invention further relates to the purposes of the compound of formula (I)-(XIX) compound or any example in the treatment.This Invention further comprises the compound of the present invention as the purposes of active therapeutic agent, especially in the disease for the treatment of RET mediations In purposes.It is comprehensive for treating intestines easily swash the invention further relates to the compound of formula (I)-(XIX) compound or any example The purposes of simulator sickness.It is used for treating cancer the invention further relates to the compound of formula (I)-(XIX) compound or any example Purposes.
Due to their potential uses in medical science, the salt of formula (I)-(XIX) compound is preferably pharmaceutically acceptable 's.Suitable pharmaceutically-acceptable salts are included by Berge, Bighley, and Monkhouse, J.Pharm.Sci. (1977) Those of 66, pp 1-19 descriptions.Cover the salt within term " pharmaceutically-acceptable salts " and refer to the nontoxic of compound of the invention Salt.The salt of disclosed compound containing basic amine or other basic functionalities can be by known in the art any suitable Prepared by method, including with inorganic acid or organic acid treatment free alkali, the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid etc., the organic acid such as acetic acid, trifluoroacetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, Oxalic acid, glycolic, salicylic acid, pyranose acid (pyranosidyl acid) (such as glucuronic acid or galacturonic acid), α- Hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or Chinese cassia tree Acid), sulfonic acid (such as p-methyl benzenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid) etc..The example of pharmaceutically-acceptable salts includes sulfate, burnt sulphur Hydrochlorate, disulfate, sulphite, bisulfites, phosphate, chloride, bromide, iodide, acetate, propionate, Caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalates, malonic acid Salt, succinate, suberate, sebacate, fumarate, maleate, butine -1,4- diacid salts, hexin -1,6- diacid Salt, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxy benzoic acid Salt, phthalate, phenyl acetate salt, phenylpropionic acid salt, PB (phenylbutrate), citrate, lactic acid Salt, gamma hydroxybutyrate, glycollate, tartrate, mandelate and sulfonate, such as xylenesulfonate, methanesulfonic acid Salt, propane sulfonic acid salt, naphthalene -1- sulfonate and naphthalene-2-sulfonic acid salt.
The salt of disclosed compound containing carboxylic acid or other acidic functionalities can also be prepared with suitable alkali.So Pharmaceutically-acceptable salts can be prepared with the alkali for providing pharmaceutically acceptable cation, it includes alkali metal salt and (is particularly sodium And potassium), alkali salt (particularly calcium and magnesium), aluminium salt and ammonium salt and the salt being made up of the acceptable organic base of physiology, The organic base such as trimethylamine, triethylamine, morpholine, pyridine, piperidines, picoline, dicyclohexyl amine, N, N'- dibenzyl second two Amine, 2 hydroxy ethylamine, double-(2- ethoxys) amine, three-(2- ethoxys) amine, procaine, dibenzyl phenylpiperidines, dehydroabietylamine, N, N'- double dehydroabietylamine, gucosamine, N- methyl glucoses osamine, collidine (collidine), choline, quinine, quinoline and alkalescence Amino acid (such as lysine and arginine).
It is not that other pharmaceutically acceptable salt can be used for preparing the compounds of this invention, and these should be regarded as forming this hair A bright further aspect.These salt, such as trifluoroacetate, although itself be not pharmaceutically acceptable, but can Salt for preparing the intermediate for being used as obtaining the compounds of this invention and its pharmaceutically-acceptable salts.
If the compound containing basic amine or other basic functionalities of the present invention is separated in a salt form, the change The corresponding free alkali form of compound can be prepared by any suitable method known in the art, including with inorganic base or organic The inorganic base or organic base of the alkali process salt, the suitably higher pKa of the free alkali form with than the compound.Similarly, If the present invention the compound containing carboxylic acid or other acidic functionalities be separated in a salt form, the compound it is corresponding Free acid form can be prepared by any suitable method known in the art, including should with inorganic acid or organic acid treatment The inorganic acid or organic acid of salt, the suitably lower pKa of the free acid form with than the compound.
Term " formula (I)-(XIX) compound " as used herein or " compound of formula (I)-(XIX) " refer to one Individual or multiple compounds according to any of formula (I)-(XIX).Formula (I)-(XIX) compound can be with solid or liquid shape Formula is present.In solid form, it can exist with crystallization or non-crystalline forms or its mixture.Those skilled in the art should Understand, pharmaceutically acceptable solvate can form crystallization or amorphization compound.In recrystallisation solvent compound, solvent molecule exists It is incorporated into crystallization process in lattice.Solvate may include nonaqueous solvents, be such as but not limited to ethanol, isopropanol, DMSO, Acetic acid, monoethanolamine or ethyl acetate, or they may include water as the solvent being attached in lattice.Its reclaimed water is to be attached to crystalline substance The solvate of solvent in lattice is commonly known as " hydrate ".Hydrate includes the hydrate of stoichiometry and containing variable Measure the composition of water.The present invention includes all such solvates.
Those skilled in the art it will be further understood that exist in crystalline form some compounds of the invention (including Its various solvate) polymorphism (that is, can be with different crystal structure presence) can be shown.These different crystal formations lead to It is commonly referred to as " polymorph (polymorph) ".The present invention includes all such polymorphs.Polymorph has identical Chemical composition, but it is different to characterize properties in accumulation (packing), geometry arrangement and other of crystalline solid state.Therefore, it is many Crystal formation thing can have different physical properties, such as shape, density, hardness, morphotropism, stability and stripping property.Polymorphic Thing generally shows different fusing points, infrared spectrum and X-ray powder diffraction figure, and it can be used for identifying.Those skilled in the art It should be appreciated that different polymorphs can enter for example, by the reaction condition or reagent that prepare used in the compound is altered or modified Produce.For example, the change of temperature, pressure or solvent may cause polymorph.In addition, a kind of polymorph can be certain Under the conditions of spontaneously change into another polymorph.
The invention further relates to 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines - 5- yls) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali and various salt some are brilliant Type.Specific salt form includes hydrochloride, esilate and sulfate.
In certain embodiments, 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines - 5- yls) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea anhydrous free alkali (compound A dissociate Alkali anhydride) crystal formation be characterised by, when using Cu K alpha rays measure when, X-ray powder diffraction (XRPD) pattern comprising choosing From at least nine following angles of diffraction：About 2.2,4.9,5.5,5.7,11.8,11.9,12.8,12.9,13.1,14.3,16.1, 16.6th, 17.1,17.2,21.2,21.3,21.9,22.0,22.7,22.8,23.1,25.3 and 25.4 degree of 2 θ.In another implementation In scheme, compound A free alkali anhydrides are characterised by, when being measured using Cu K alpha rays, X-ray powder diffraction (XRPD) pattern is comprising selected from following at least eight angles of diffraction or at least seven angles of diffraction or at least six angles of diffraction or at least Five angles of diffraction or at least four angles of diffraction：About 2.2,4.9,5.5,5.7,11.8,11.9,12.8,12.9,13.1,14.3, 16.1st, 16.6,17.1,17.2,21.2,21.3,21.9,22.0,22.7,22.8,23.1,25.3 and 25.4 degree of 2 θ.Another In individual embodiment, compound A free alkali anhydrides are characterised by, when being measured using Cu K alpha rays, x-ray powder spreads out (XRPD) pattern is penetrated comprising at least selected from three following angles of diffraction：About 2.2,4.9,5.5,5.7,11.8,11.9,12.8, 12.9th, 13.1,14.3,16.1,16.6,17.1,17.2,21.2,21.3,21.9,22.0,22.7,22.8,23.1,25.3 and 25.4 degree of 2 θ.
In still another embodiment, compound A free alkali anhydrides are characterised by, when using CuKαRay is surveyed During amount, X-ray powder diffraction (XRPD) pattern is comprising about 5.7,11.9,12.9,14.3, the 16.1 and 23.1 degree of 2 θ angle of diffraction. In still another embodiment, compound A free alkali anhydrides are characterized by penetrating with the substantial consistent X of Fig. 1 Line powder diffraction (XRPD) pattern.
In other embodiments, compound A free alkalis anhydride is characterised by that Raman spectrum is included and is selected from following peak At least nine peaks of position：About 409,442,467,585,708,743,773,790,851,904,950,1005,1247, 1314、1330、1397、1435、1469、1492、1530、1577、1623、1653、1710、2940cm-1.In another embodiment party In case, compound A free alkali anhydrides are characterised by that Raman spectrum includes at least eight peaks or extremely selected from following peak position Few seven peaks or at least six peaks or at least five peaks or at least four, three peaks：About 409,442,467,585,708,743, 773、790、851、904、950、1005、1247、1314、1330、1397、1435、1469、1492、1530、1577、1623、 1653、1710、2940cm-1.In another embodiment, compound A free alkalis anhydride is characterised by Raman spectrum bag Containing at least three peaks selected from following peak position：About 409,442,467,585,708,743,773,790,851,904,950, 1005、1247、1314、1330、1397、1435、1469、1492、1530、1577、1623、1653、1710、2940cm-1。
In still another embodiment, compound A free alkali anhydrides are characterised by that Raman spectrum is included and are located at About 1247,1314,1330,1435,1469,1492,1530,1577,1623,1653,1710,2940cm-1Peak.Still another In one embodiment, compound A free alkali anhydrides are characterized by and the substantial consistent Raman spectrums of Fig. 2.
In further embodiment, compound A free alkali anhydrides are characterized by substantially consistent with Fig. 3 Differential scanning calorimetry trace and/or with Fig. 4 substantially consistent thermogravimetry traces.
In still further embodiment, it should be understood by one skilled in the art that compound A free alkalis are anhydrous Thing is characterized by characterizing any combination of the analyze data of foregoing embodiments.For example, in one embodiment, changing Compound A free alkali anhydrides be characterized by with Fig. 1 substantially consistent X-ray powder diffraction (XRPD) patterns and with figure 2 substantially consistent Raman spectrums and with Fig. 3 substantially consistent differential scanning calorimetry traces and substantially consistent with Fig. 4 Thermogravimetry trace.In another embodiment, compound A free alkalis anhydride is characterized by and Fig. 1 essence Upper consistent X-ray powder diffraction (XRPD) pattern and with Fig. 2 substantially consistent Raman spectrums.In another embodiment In, compound A free alkali anhydrides are characterized by and substantial consistent X-ray powder diffraction (XRPD) patterns of Fig. 1 With with Fig. 3 substantially consistent differential scanning calorimetry traces.In another embodiment, compound A free alkalis anhydride Be characterized by with Fig. 1 substantially consistent X-ray powder diffraction (XRPD) patterns and with Fig. 4 substantially consistent thermogravimetrics Amount analysis trace.In another embodiment, compound A free alkalis anhydride is characterized by including and penetrated using CuK α Line measurement about 5.7,11.9,12.9,14.3, X-ray powder diffraction (XRPD) pattern of 16.1 and 23.1 degree of 2 θ angle of diffraction, With comprising positioned at about 1247,1314,1330,1435,1469,1492,1530,1577,1623,1653,1710,2940cm-1's The Raman spectrum at peak.In another embodiment, compound A free alkalis anhydride is characterized by including using Cu K Alpha ray measurement about 5.7,11.9,12.9,14.3, X-ray powder diffraction (XRPD) pattern of 16.1 and 23.1 degree of 2 θ angle of diffraction With with Fig. 3 substantially consistent differential scanning calorimetry traces.In another embodiment, compound A free alkalis anhydride It is characterized by comprising about 5.7 measured using Cu K alpha rays, 11.9,12.9,14.3,16.1 and 23.1 degree of 2 θ diffraction Angle X-ray powder diffraction (XRPD) pattern and with Fig. 4 substantially consistent thermogravimetry traces.
It should be appreciated that when the angle of diffraction (being represented with spending 2 θ) that XRPD patterns are included is within ± 0.3 degree of 2 θ of designated value, Then the XRPD patterns include the angle of diffraction of " about " value specified herein.Further, those skilled in the art know and understood, used Device, humidity, temperature, the orientation of powder crystal and be related to obtain X-ray powder diffraction (XRPD) pattern other parameters can With some changes of the outward appearance, intensity and linear position that cause diffracting spectrum.It will be understood by those skilled in the art that provided herein is Have with the X-ray powder diffraction figure case of Fig. 1,5,9,13,17,21,25,29,33 or 37 " substantially consistent " for expression with carrying For the XRPD patterns of the isomorphous compound of compound phase of the XRPD patterns of Fig. 1,5,9,13,17,21,25,29,33 or 37. That is, the XRPD patterns may be identical with Fig. 1,5,9,13,17,21,25,29,33 or 37, or more likely it may some be poor It is different.Such XRPD patterns may might not show each lines of any of diffraction pattern shown in this article, and/or may Show the different caused slight variations in the displacement of outward appearance, intensity or the line of condition that data are obtained due to being related to.This Art personnel can determine whether the sample of crystalline compounds has with being disclosed herein by comparing their XRPD patterns Identic form or different forms.For example, those skilled in the art can by 1- (2- (4- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- Base) urea free alkali sample XRPD patterns it is overlapping with Fig. 1, and be readily determined using the know-how and knowledge of this area Whether the XRPD patterns of sample are substantially consistent with the XRPD patterns of compound A free alkali anhydrides disclosed herein.If should XRPD patterns are substantially consistent with Fig. 1, then the sample form easily and can be precisely determined as and compound A disclosed herein Free alkali anhydride has identical form.It should be appreciated that the peak included when Raman spectrum is (with cm-1Represent) designated value ± 5.0cm-1Within when, then the Raman spectrum includes the peak of " about " value specified herein.Further, those skilled in the art are also known And understand, the other parameters that device used, humidity, temperature, the orientation of powder crystal and being related to obtain Raman spectrum can be made Into some changes of the outward appearance, intensity and peak position of the spectrum.It will be understood by those skilled in the art that with provided herein is Fig. 2,6, 10th, 14,18,22,26,30,34 or 38 the Raman spectrum of " substantially consistent " for represent to have with provide Fig. 2,6,10,14,18, 22nd, the Raman spectrum of the isomorphous compound of the compound phase of 26,30,34 or 38 Raman spectrum.That is, the Raman spectrum may It is identical with Fig. 2,6,10,14,18,22,26,30,34 or 38, or more likely it may some differences.Such Raman light Spectrum may might not show each peak of any of spectrum shown in this article, and/or may show due to being related to acquisition number According to condition difference cause the slight variation in the displacement of outward appearance, intensity or the peak.Those skilled in the art can pass through Compare their Raman spectrum to determine, whether the sample of crystalline compounds is with form disclosed here identical form or not Same form.For example, those skilled in the art can be by 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- Methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali sample Raman spectrum is overlapping with Fig. 2, and using this area know-how and knowledge be readily determined sample Raman spectrum whether It is substantially consistent with the Raman spectrum of compound A free alkali anhydrides disclosed herein.
Formula (I)-(XIX) compound or its salt can with stereoisomeric forms in any ratio exist (for example, its contain it is one or more Asymmetric carbon atom).The single stereoisomer (enantiomter and diastereoisomer) and these mixture bags Include within the scope of the present invention.The scope of the present invention includes stereoisomer mixture and the enantiomter of purifying or mapping is different The mixture of structure body/diastereoisomer enrichment.
Similarly, it should be understood that formula (I)-(XIX) compound or its salt can be with different from shown mutual in chemical formula Become isomeric form to exist, these are also included within the scope of the present invention.For example, when formula (I)-(XIX) compound is described as During containing pyridin-2-ones part, then the corresponding 2 hydroxy pyrimidine dynamic isomer is also included within the scope of the present invention.Should When the understanding present invention includes all combinations and the subset of all special groups defined above.
It will be understood by those skilled in the art that the derivative of some protections of formula (I)-(XIX) compound, it can be at it Prepared after the preceding or last deprotection stage, thus can not have pharmacological activity, but in some cases, can be with mouth Clothes or parenteral, and be metabolized to form the compound of the invention with pharmacological activity afterwards in vivo.Therefore, so Derivative can be described as " prodrug ".Further, some compounds of the invention can serve as other compounds of the present invention Prodrug.The derivative and prodrug of the protection of all compounds of the invention are included within the scope of the present invention.
The example of the suitable prodrug of the compounds of this invention is described in Drugs of Today, Volume 19, Number9, 1983, pp 499-538 and Topics in Chemistry, Chapter 31, pp 306-316 and in " Design of In Prodrugs " by H.Bundgaard, Elsevier, 1985, Chapter 1.It should also be appreciated by one skilled in the art that working as , can be by known to those skilled in the art for " precursor portions when suitable functional group is present within the compound of the present invention (pro-moieties) described in " some parts (such as H.Bundgaard exists " Design of Prodrugs ") it is placed in In suitable functional group.Preferred " precursor portions " of the compound of the present invention include：The ester of formula (I)-(XIX) compound, Carbonic ester, half ester, phosphate, nitro ester, sulfuric ester, sulfoxide, acid amides, carbamate, azo (azo-), phosphamide, glucosides, Ether, acetal and ketal derivatives.
One or more in the compound of the invention of prodrug those skilled in the art's progress being made following are administered： (a) initiation of the compound in vivo is modified；(b) acting duration of the compound in vivo is modified；(c) modification should The transport or distribution of compound in vivo；(d) dissolubility of the compound in vivo is modified；Overcome the compound to be met with (e) The side effect of chance or other difficulties.
Present invention additionally comprises the compound of isotope marks, it is same with those compound phases enumerated in formula (I)-(XIX), Except the fact that, i.e., but one or more atoms by the atomic mass with the atom being generally found different from nature Or the atom of mass number is substituted.The example of the compound of the present invention and its isotope of pharmaceutically-acceptable salts, which can be mixed, to be included Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, the isotope of iodine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl、123I and125I。
The compounds of the invention of other isotopes containing aforementioned isotopes and/or other atoms and the compound Pharmaceutically-acceptable salts are within the scope of the present invention.The compound of the invention of isotope marks, such as it is radioactivity is same Position element is (such as3H or14C those compounds therein) are mixed, for medicine and/or substrate tissue measure of spread.Tritium generation (i.e. ,3H) and carbon-14 (i.e.,14C) isotope, because they are easily prepared and detection, therefore is particularly preferred.11C and18F isotopes Particularly for PET (positron emission tomography), and125I isotopes are (Single Photon Emission Computed particularly for SPECT Tomography), all of which is used for Brian Imaging.Further, with higher isotope (such as deuterium, i.e.2H substitution), because it is bigger Metabolic stability, it is possible to provide some treatment advantages, such as the volume requirements of increased Half-life in vivo or reduction, therefore, Certain situation is probably preferred.The compound of the formula (I) of isotope marks and according to the present invention compound can generally lead to Cross following prepared：Implement operation disclosed in following proposal and/or embodiment, with the isotope labeling reagent being readily available Instead of nonisotopic labels reagent.
Definition
Term is used in its acceptable implication.Following definitions are intended to illustrate and non-limiting defined term.
Term " alkyl " as used herein represents saturation, straight or branched hydrocarbon part.Term " (C1-C6) alkyl " refer to Moieties containing 1 to 6 carbon atoms.Exemplary alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, Normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group and hexyl.When term " alkyl " with other substituted radicals combines such as " halogen Generation (C1-C4) alkyl " or " hydroxyl (C1-C4) alkyl " in use, the term " alkyl " is intended to divalent straight or branched-chain hydrocarbons Base, wherein tie point are via moieties.Term " halo (C1-C4) alkyl " be intended to refer in the alkane containing 1 to 4 carbon atom One or more carbon atoms of base section (its be straight or branched carbon-based group) have it is one or more can be with identical or different The group of halogen atom.For " halo (the C in the present invention1-C4) alkyl " example of group includes, but are not limited to-CHF2(two Methyl fluoride) ,-CF3(trifluoromethyl) ,-CCl3(trichloromethyl), the fluoro ethyls of 1,1- bis-, 2,2,2- trifluoroethyls and hexafluoro isopropyl Base.For " hydroxyl (the C in the present invention1-C4) alkyl " example of group includes but is not limited to hydroxymethyl, hydroxyethyl and hydroxyl Base isopropyl.
" alkoxy " refers to the group containing the alkyl defined above that atom connection is connected by oxygen.Term " (C1-C4) alcoxyl Base " refers to at least one that atom connection is connected by oxygen and the straight or branched alkyl of at most 4 carbon atoms.For the present invention In exemplary " (C1-C4) alkoxy " group includes, but are not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, sec-butoxy, isobutoxy and tert-butoxy.
When term " alkoxy " and other substituted radicals are applied in combination, such as " halo (C1-C6) alkoxy ", " hydroxyl (C2-C4) alkoxy " or " (C1-C4) alkoxy (C2-C4) alkoxy ", term " alkoxy " is intended to divalent straight or side chain Alkyl, wherein tie point are the moieties that atom is connected via oxygen.Term " halo (C1-C6) alkoxy " refer to at least one And the one or more halogen atoms being connected with one or more carbon atoms of at most 6 carbon atoms (it can be with identical or different) Straight or branched alkyl, wherein the group be via oxygen connection atom connection.Exemplary " halo (C for the present invention1- C6) alkoxy " group includes, but are not limited to-OCHF2(difluoro-methoxy) ,-OCF3(trifluoromethoxy) and-OCH (CF3)2(six Fluorine isopropoxy)." hydroxyl (C for the present invention2-C4) alkoxy " example of group includes, but are not limited to 2- hydroxyl-oxethyls With 2- hydroxyl isopropoxies." (C for the present invention1-C4) alkoxy (C2-C4) alkoxy " example of group includes, but do not limit It is different in 2- methoxy ethoxies, 2- ethoxy ethoxies, 2- isopropoxies ethyoxyl, 2- methoxyl groups isopropoxy and 2- ethyoxyls Propoxyl group.
Term " cycloalkyl " as used herein refers to containing specified the non-aromatic of carbon number, saturation, the hydrocarbon ring of ring-type.Art Language " (C3-C6) cycloalkyl " refer to the non-aromatic cyclic hydrocarbon ring with three to six ring carbon atoms.For the exemplary of the present invention " (C3-C6) " group includes cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl to cycloalkyl.
Term " cycloalkyloxy-" as used herein refers to contains cycloalkyl defined above via oxygen connection atom connection The group of group.Exemplary " (C for the present invention3-C8) cycloalkyloxy " and group include ring propoxyl group, cyclobutoxy group, ring penta Epoxide, cyclohexyloxy, cycloheptyl epoxide and ring octyloxy.
" 4- to 6- circle heterocycles alkyl ", which is represented, as used herein includes the non-aromatic, group of monovalent monocyclic group or portion Point, it is that saturation or part are undersaturated, containing 4,5 or 6 annular atoms, it include one or two independently selected from oxygen, The hetero atom of sulphur and nitrogen.Exemplary example for 4- to the 6- circle heterocycles alkyl groups of the present invention includes, but are not limited to nitrogen Azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolines It is base, thiazolinyl, tetrahydrofuran base, dihydrofuran base, 1,3- dioxolanyls, piperidyl, piperazinyl, morpholinyl, thio Quinoline base, THP trtrahydropyranyl, dihydro pyranyl, 1,3- alkyl dioxins, 1,4- alkyl dioxins, 1,3- oxygen thias cyclopenta, 1,3- oxygen Thia cyclohexyl (oxathianyl), 1,3- dithiane base, 1,4- oxygen thias cyclopenta, 1,4- oxygen thia cyclohexyl and 1,4- bis- Thiophene alkyl.
" 5- or 6- unit's heteroaryls " represents the group comprising aromatics monovalent monocyclic group or part as used herein, contains 5 or 6 annular atoms, including at least one carbon atom and 1 to 4 hetero atom independently selected from nitrogen, oxygen and sulphur.Selected 5- Unit's heteroaryl group contains a nitrogen, oxygen or sulphur ring hetero atom, and optionally containing 1,2 or 3 other nitrogen ring atoms.It is selected The 6- member groups selected contain 1,2 or 3 azo-cycle hetero atoms.Exemplary reality for 5- the or 6- unit's heteroaryl groups of the present invention Example includes, but are not limited to furyl, thienyl, pyrrole radicals, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyls, thiazole Base, isoxazolyls, isothiazolyl, oxadiazolyls, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals and triazine radical.
Term " halogen " and " halo " represent chlorine, fluorine, bromine or iodine substituent." hydroxyl (Hydroxy) " or " hydroxyl (hydroxyl) " it is intended to refer to group-OH.Term " cyano group " as used herein refers to group-CN.
Term " optionally substituted " as used herein, which refers to group such as alkyl, cycloalkyl, phenyl or heteroaryl, to be Unsubstituted or described group can be replaced by one or more substituents such as definition.Group may be selected from largely replacing wherein In the case of for group, selected group can be with identical or different.
Term " independently " refers to wherein more than one substituent and is selected from a large amount of possible substituents, and those substituents can phase It is same or different.Formula (I)-(XIX) various groups and alternatively the determining for substituted radical provided is provided throughout the specification Justice is intended to respectively particularly described each classes of compounds disclosed herein, and one or more classes of compounds base Group.The scope of the present invention includes any combination that these groups and substituted radical are defined..
" pharmaceutically acceptable (pharmaceutically acceptable) " refers to it in rational medical judgment scope, is adapted for contact with the mankind With the tissue of animal without excessive toxicity, stimulation or other problems or complication, with rational benefit/risk than match that A little compound, material, composition and formulations.
Term " pharmaceutically-acceptable salts " as used herein refers to the reservation desired bioactivity of motif compound, and Show the salt of the undesirable toxicological effect of minimum.These pharmaceutically-acceptable salts can compound be finally separating with it is pure Change process situ prepare, or by individually by the purifying compound of its free acid or free alkali form respectively with suitable alkali Or prepared by acid reaction.
Pharmaceutical composition
The present invention further provides pharmaceutical composition (also referred to as pharmaceutical preparation), it includes formula (I)-(XIX) compound Or its pharmaceutically-acceptable salts and one or more excipient (being also referred to as carrier and/or diluent in pharmaceutical field).From with system The other compositions of agent it is compatible and to recipient (i.e. patient) it is harmless in the sense that say, excipient is pharmaceutically acceptable.
Suitable pharmaceutically acceptable excipient includes the excipient of following types：Diluent, filler, adhesive, collapse Solve agent, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, flavoring Agent, odor mask, colouring agent, anti-caking agent, NMF, chelating agent, plasticizer, tackifier, antioxidant, preservative, stabilizer, table Face activating agent and buffer.It should be understood by those skilled in the art that some pharmaceutically acceptable excipient can provide more than one Function, and it can provide other functions, this depend on the excipient be present in preparation number and what also has its He is present in said preparation composition..
Those skilled in the art possess this area knowledge and technology, so as to select suitably to measure it is suitable pharmaceutically Acceptable excipient is used for the present invention.In addition, those skilled in the art can obtain the pharmaceutically acceptable excipient of description and can use In the ample resources of the suitable pharmaceutically acceptable excipient of selection.Example includesRemington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
Pharmaceutical composition of the present invention is prepared using technology well known by persons skilled in the art and method.It is usually used in this area Certain methods description existsRemington's Pharmaceutical SciencesIn (Mack Publishing Company).
According to another aspect of the present invention there is provided a kind of method for preparing pharmaceutical composition, including by formula (I)-(XIX) Compound or its pharmaceutically-acceptable salts mix with least one excipient (or blending).
Pharmaceutical composition can contain the unit dosage form of the active component of scheduled volume for each unit dose.It is such Unit can be containing treatment effective dose formula (I)-(XIX) compound or its pharmaceutically-acceptable salts, it is or a certain proportion of Formula (I)-(XIX) for the treatment of effective dose compound or its pharmaceutically-acceptable salts, so as to can be administered in the given time many Individual unit dosage form is to reach desired treatment effective dose.It is preferred that unit dose formulations be it is hereinbefore enumerate contain Those of the daily dosage or sub-doses of active component or its appropriate ratio.In addition, such pharmaceutical composition can pass through Known to pharmaceutical field prepared by any method.
Pharmaceutical composition may be adapted to be administered by any suitable approach, for example, by oral administration (including in cheek or sublingual), Rectum, nose, part (including in cheek, sublingual or transdermal), vagina or parenteral (including subcutaneous, intramuscular, intravenous or intracutaneous) way Footpath is administered.Such composition can be prepared by any method known in the art, for example, by make active component with it is a kind of or A variety of excipient are combined.
When suitable for being administered orally, pharmaceutical composition can for discrete unit such as tablet or capsule, powder or particle, Solution or suspension, edible foam or whipping agent (whip) in aqueous or non-aqueous liquid, or oil-in-water liq breast Agent or water-in-oil liquid emulsion.The compound or its salt of the present invention or the pharmaceutical composition of the present invention can also be incorporated into sugar Really, in waffle (wafer) and/or lingual ribbon type (tongue tape) preparation, for the drug administration as " quick dissolving ".
For example, oral administration in the form of a tablet or capsule, can be by active medicine component and oral, nontoxic medicine Inert carrier such as ethanol, glycerine, water etc. is subjected on to mix.Powder agent or granule are prepared as follows：By compound Suitable fine sizes are ground to, then with the such as edible carbohydrate of the pharmaceutical carrier through similar grinding (as example Starch or mannitol) mixing.Flavouring, preservative, dispersant and colouring agent also may be present.
Capsule is prepared as follows：Mixture of powders is prepared as described above, the gelatin or non-bright of shaping is subsequently filled In glue shell.Can be by glidant and the poly- second two of lubricant such as cataloid, talcum, magnesium stearate, calcium stearate, solid Alcohol is added in mixture of powders, and operation is filled afterwards.Disintegrant or solubilizer such as agar, calcium carbonate can also be added Or sodium carbonate is to improve drug availability when capsule is ingested.
Moreover, when being desired or needed for, suitable adhesive, lubricant, disintegrant and colouring agent can also be incorporated into In mixture.Suitable adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural Glue and rubber polymer such as Arabic gum, tragacanth, sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax etc..In these agent The lubricant used in type includes enuatrol, odium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc..Disintegrant Include, but are not limited to starch, methylcellulose, agar, bentonite, xanthans etc..
Tablet is prepared as follows：Mixture of powders, granulation or pre- tabletting are for example prepared, lubricant and disintegrant is added, It is then pressed into tablet.Mixture of powders is prepared as follows：By the compound through properly crushing and diluent as described above or Matrix mix, and with optional adhesive (such as carboxymethyl cellulose and alginate, gel or polyvinylpyrrolidone), Solution retarding agents (such as paraffin), sorbefacient (such as quaternary amine) and/or absorbent (such as bentonite, kaolin or phosphorus Sour dicalcium) mixing.Mixture of powders can pelletize as follows：Wet adhesive such as syrup, gelatinized corn starch, Arabic glue, fiber Plain solution or polymer solution, then extruding sieving.As selectable method of granulating, mixture of powders can pass through tablet press machine To handle, the pre- tabletting not exclusively shaped is caused to be broken into particle.Can be by adding stearic acid, stearate, talcum or ore deposit The mode of thing oil is lubricated to particle, to prevent and tablet forming dies adhesion.Then, it is the mixture of lubrication is tabletted Agent.The compound or salt of the present invention can also be combined with the inert carrier of free-flowing, and not suffer from granulation or pre- tabletting Direct pressing piece agent in the case of step.Transparent or opaque protectiveness consisting of the following can be provided to be coated：By Isolation coat layer, the coatings formed by sugar or polymer and the bright coatings formed by wax of shellac formation.It will can contaminate Material is added in these coatings to distinguish different dosage.
Oral fluids such as solution, syrup and elixir according to dosage unit form can be prepared, so that given Measure the active component containing scheduled volume.Syrup can be by being dissolved in the water through suitable flavoring by the compound or its salt of the present invention Prepared in solution, and elixir is prepared by using nontoxic containing alcohol medium.Suspending agent can by by the present invention change Compound or its salt are dispersed in nontoxic medium to prepare.Can also add solubilizer and emulsifying agent (such as ethoxylation Isooctadecanol and polyoxyethylene sorbitol ether), preservative, flavoring additive (such as peppermint oil, natural sweetener, saccharin or its Its artificial sweetener) etc..
When appropriate, microencapsulation can be carried out to the dosage unit preparations for oral administration.Can also be for example by inciting somebody to action Particulate matter, which is coated or is embedded into polymer, wax etc., carrys out preparation of preparation, to extend or maintain release.
In the present invention, for delivering pharmaceutical composition, tablet and capsule are preferred.
In some embodiments, the present invention relates to include 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Pharmaceutical composition.In another embodiment, the present invention relates to include 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea The pharmaceutical composition of free alkali, 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- of the weight of wherein at least 10% Base) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Exist with compound A free alkalis anhydride as described herein.In another embodiment, the present invention relates to include 1- (2- (4- Ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methyl-props of 1,1,1- tri- Alkane -2- base) isoxazole -3-bases) urea free alkali pharmaceutical composition, the weight of wherein at least 20% or at least 30% weight or At least 40% weight or at least 50% weight or at least 60% weight or at least 70% weight or at least 80% weight or extremely 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- of few 90% weight (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali it is anhydrous with compound A free alkalis described herein Thing is present.In another embodiment, the present invention relates to include 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Pharmaceutical composition, the weight of wherein at least 95% or at least 96% weight or at least 97% weight or at least 98% weight or 1- (2- (the 4- ethoxies of at least 99% weight or at least 99.5% weight or at least 99.8% weight or at least 99.9% weight Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- of 1,1,1- tri- Base) isoxazole -3-bases) free alkali of urea exists with compound A free alkalis anhydride described herein.
In another embodiment, the present invention relates to comprising 1- (2- (4- ethyoxyl -6- oxos -1,6- dihydropyridine - 3- yls) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea it is free The pharmaceutical composition of alkali, the free alkali wherein no more than 90% weight is amorphous.In another embodiment, originally Invention is related to comprising 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) urea free alkali pharmaceutical composition, wherein no more than 80% Weight or no more than 70% weight or no more than 60% weight or no more than 50% weight or no more than 40% weight or not It is amorphous more than 30% weight or no more than 20% weight or no more than the free alkali of 10% weight.In another implementation In scheme, the present invention relates to include 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) urea free alkali pharmaceutical composition, wherein No more than 5% weight or no more than 4% weight or no more than 3% weight or no more than 2% weight or no more than 1% weight Amount is amorphous no more than 0.5% weight or no more than 0.2% weight or no more than the free alkali of 0.1% weight 's.
In another embodiment, the present invention relates to comprising 1- (2- (4- ethyoxyl -6- oxos -1,6- dihydropyridine - 3- yls) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea it is free The pharmaceutical composition of alkali, wherein no more than 90% weight 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) - 4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali with not The form for being same as compound A free alkali anhydrides described herein is present.In another embodiment, the present invention relates to include 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (fluoro- 2- first of 1,1,1- tri- Base propane -2- base) isoxazole -3-bases) urea free alkali pharmaceutical composition, wherein no more than 80% weight or be no more than 70% weight or no more than 60% weight or no more than 50% weight or no more than 40% weight or no more than 30% weight, Or no more than 20% weight or no more than the 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- of 10% weight Base) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Exist in the form of different from compound A free alkali anhydrides as described herein.In another embodiment, the present invention relates to Include 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- Fluoro- 2- methylpropanes -2- base) isoxazole -3-bases) urea free alkali pharmaceutical composition, wherein no more than 5% weight or not More than 4% weight or no more than 3% weight or no more than 2% weight or no more than 1% weight or no more than 0.5% weight Amount or no more than 0.2% weight or no more than 0.1% weight 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines - 3- yls) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea it is free Alkali exists in the form of different from compound A free alkali anhydrides as described herein.
Term " treatment " as used herein refers to mitigates specific in the patient or subject for previously suffering from or being diagnosed Illness, eliminates or reduces one or more symptoms of the illness, slows down or eliminates the progress of the illness and prevention or prolong The recurrence of the slow illness.
The present invention provides a kind of method for the mammal (the particularly mankind) treated with following illnesss：Intestines easily swash is integrated Levy (IBS), including diarrhea predominance type, constipation leading type or alternating bowel movement pattern, feature aerogastria, functional consitipation, function Property diarrhoea, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, Functional Esophageal Disorders, feature Depressed rats, functional anorectal pain, inflammatory bowel disease, proliferative diseases for example non-small cell lung cancer, hepatocellular carcinoma, Colorectal cancer, medullary carcinoma of thyroid gland, follicular thyroid carcinoma, undifferentiated thyroid carcinoma, papillary thyroid carcinoma, brain tumor, peritonaeum Chamber cancer, solid tumor, other lung cancer, head and neck cancer, glioma, neuroblastoma, Von Hipple-Lindau syndromes and Cancer at kidney neoplasms, breast cancer, carcinoma of fallopian tube, oophoroma, transitional-cell carinoma, prostate cancer, esophagus and Esophagogastric junction, Cancer of bile ducts and gland cancer or its combination.Such treatment is included to the mammal (such as the mankind) drug treatment effective dose The step of formula (I)-(XIX) compound or its pharmaceutically-acceptable salts.Treatment is further comprising the steps of：To the mammal The compound or the medicine group of its pharmaceutically-acceptable salts containing formula (I)-(XIX) of (the particularly mankind) drug treatment effective dose Compound.
Term " effective dose " as used herein guide the tissue that hair such as researcher or clinician seek, system, The medicine or the amount of medicament of the biology or medicinal response of animal or people.
Term " therapeutically effective amount " refers to compared with the corresponding subject for not receiving the amount, makes disease, illness or side reaction Improvedd treatment, healing, prevention or alleviation, or reduce any amount of the tempo of disease or illness.The term also exists Include the amount of effectively enhancing normal physiological function in the range of it.For being used in treatment, formula (I)-(XIX's) of therapeutically effective amount Compound and its salt can be administered as the form of chemical raw material (raw chemical).In addition, active component can conduct Pharmaceutical composition is present.For being used in treatment, although formula (I)-(XIX) compound of therapeutically effective amount or its can pharmaceutically connect Can be possible as the form administration of chemical raw material by salt, but it is usually as pharmaceutical composition or the active component of preparation In the presence of.
The accurate therapeutically effective amount of the compound or its salt of the present invention will depend on many factors, include but is not limited to, The age of subject (patient) to be treated and body weight, the accurate illness and its seriousness, pharmaceutical formulations/composition for needing treatment Property, and method of administration, and most judge to determine by attending doctor or animal doctor at last.Generally, give the formula (I) for the treatment of- (XIX) compound or the scope of its pharmaceutically-acceptable salts for daily about 0.1 to 100mg/kg recipients (patient, lactation move Thing) body weight, more generally scope is daily 0.1 to 10mg/kg body weight.Acceptable daily dose can be about 0.1 to about 1000mg/ days, and preferably about 1 to about 100mg/ days.The amount can be given with daily single dose or with daily for several times (such as 2,3,4,5 or more) sub-doses are given, so that total daily dose is identical.The effective dose of salt can be according to formula (I) certain proportion of-(XIX) compound effective dose itself is determined.Similar dosage for treatment is for treatment this paper Should be suitable for the other illnesss referred to.Generally, the determination for being adapted to dosage can be easily by medical science or pharmaceutical field Technical staff obtain.
The compound of the present invention can be used alone or be used with one or more combination with other therapeutic agents.Therefore, this hair It is bright that a kind of combination is provided, its compound comprising formula (I)-(XIX) or its pharmaceutically-acceptable salts and one or more control Treat agent.Such combination can individualism (wherein each active material is in single composition) or the active material to combine Composition is present.
The compound of the present invention particularly can improve the compound activity or Deal with Time with other therapeutic agents The pharmaceutical agent combinations or co-administered of (time of disposition).Included applying at least one according to the combination treatment of the present invention Plant the compounds of this invention and using at least one other treatment method.In one embodiment, according to the combination of the present invention Therapy includes applying at least one compound and operation therapy of the invention.In one embodiment, according to the present invention Combination treatment include apply at least one compound and radiotherapy of the invention.In one embodiment, according to this hair Bright combination treatment includes applying at least one the compounds of this invention and at least one supporting treatment reagent (for example, at least one Antiemetic).In one embodiment, according to the present invention combination treatment include apply at least one compound of the invention with And other at least one chemotherapeutics.In a specific embodiment, the present invention includes applying at least one change of the invention Compound and at least one antitumor agent.In still another embodiment, the present invention includes a kind of therapeutic scheme, wherein this public affairs The RET inhibitor opened is not active or active not notable in itself, but when it (may as monotherapy with other therapies It is active may also be without activity) combination when, the combination provides useful treatment results.
Term " co-administered " as used herein and its derivative words refer to be administered simultaneously or by it is any individually successively in the way of RET inhibiting compounds as described herein and other active components is administered, particularly becomes known for treating cancer (including chemotherapy And radiotherapy in the treatment) those components.Term other active components as used herein are worked as including known or confirmation is administered to needs Any compound or therapeutic agent of beneficial property are shown during the patient for the treatment of cancer.Preferably, if the administration is not same When, then the compound was administered in the time closer to each other.In addition, no matter whether the compound is given with same one dosage type low temperature Medicine is all inessential, such as a kind of compound can locally be administered and another compound can be taken orally.
Generally, the active any antitumor agent of sensitiveness (susceptible) tumour to treatment can be at this Invent co-administered in specific treatment of cancer.The example of such reagent can be in Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman(editors),6th edition(February 15,2001), found in Lippincott Williams＆Wilkins Publishers.Those skilled in the art being capable of basis Medicine and the specific features of involved cancer differentiate useful pharmaceutical agent combinations.Typical antineoplastic for the present invention includes, But it is not limited to：Anti- micro-pipe agent, such as diterpene-kind compound and vinca alkaloids；Platinum coordination complex；Alkylating agent, such as mustargen (nitrogen mustard), oxynitride phosphor ring class (oxazaphosphorine), alkylsulfonate, nitroso ureas and triazenes； Antibiotic agent, such as anthracycline antibiotic (anthracyclin), D actinomycin D and bleomycin；Topoisomerase II suppresses Agent, such as epipodophyllotoxin；Antimetabolite, such as purine and pyrimidine analogue and anti-folic acid compound；Topoisomerase I suppresses Agent, such as camptothecine；Hormone and hormone analogs；Dnmt rna inhibitor, such as azacitidine and Decitabine；Letter Number transduction pathway inhibitor；Nonreceptor tyrosine kinase angiogenesis inhibitors；Immunotherapeutic agent；Promote apoptosis agent；And cell week Phase signal inhibitor.
Generally, any chemotherapeutics active to the sensitiveness knurl treated can be combined with the compound of the present invention Use, condition is that the specific reagent is clinically compatible with the therapy of the compound using the present invention.Typical case for the present invention Antitumor agent includes, but are not limited to：Alkylating agent, antimetabolite, antitumor antibiotics, antimitotic agent, nucleoside analog, open up Flutter isomerase I and II inhibitor, hormone and hormone analogs；Retinoids, histone deacetylase inhibitors；Signal transduction Pathway inhibitor, including cell growth or growth factor function inhibitor, angiogenesis inhibitors and serine/threonine or Other kinase inhibitors；Cell cycle protein dependent kinase inhibitor；Antisense therapy and immunotherapeutic agent, including monoclonal are anti- Body, vaccine or other biological preparation.
Nucleoside analog is those for changing into triphosphate deoxy-nucleotide and being incorporated into instead of cytimidine in the DNA of duplication Compound.Dnmt rna is covalently bond in the base of the modification, the DNA methylation for causing enzyme to inactivate and reduce.Core The example of glycosides analog includes azacitidine and Decitabine, and it is all used to treat myeloproliferative disorder.Histone takes off second Acyl enzyme (HDAC) inhibitor includes Vorinostat, for treating skin T cell lymphoma.HDAC passes through histone deacetylase Act on modifying chromatin.In addition, they have various substrate specificities, including various transcription factors and signaling molecule.Other Hdac inhibitor is researched and developed.
Signal transduction pathway inhibitor is blocking or those inhibitor for suppressing chemical process, and the chemical process causes carefully Intracellular changes.As used herein, the change is cell propagation or differentiation or survived.Signal transduction pathway for the present invention Inhibitor includes, but not limited to receptor tyrosine kinase, nonreceptor tyrosine kinase, SH2/SH3 domains blocking agent, silk ammonia Acid/threonine kinase, phosphatidylinositols -3-OH kinases, inositol signal transduction and the inhibitor of Ras oncogenes.Signal transduction leads to Road inhibitor can be applied in combination with the compound of the invention in above-mentioned composition and method.
Receptor kinase angiogenesis inhibitors can be used in the present invention.It is related to VEGFR and TIE-2 angiogenesis suppression Preparation is discussed in above-mentioned be directed in signal transduction inhibitor (both receptor tyrosine kinases).Other inhibitor can It is applied in combination with the compound with the present invention.For example, anti-VEGF antibody, its nonrecognition VEGFR (receptor tyrosine kinase), but knot Close part；Integrin (αvβ3) micromolecular inhibitor, its suppress angiogenesis；Endostatin and angiostatin (non-RTK) Also it is proved to can be used for the compound with the present invention to combine.One example of VEGFR antibody is bevacizumab
The various inhibitors of growth factor receptors are researched and developed, and including ligand antagonists, antibody, tyrosine-kinase enzyme level Agent, ASON and fit.These any growth factor receptor inhibitors can be shared with the compound group of the present invention in In arbitrary composition as described herein and method/purposes.HerceptinIt is the anti-erbB2 of growth factor function One example of antibody inhibition.The example of the anti-erbB2 antibody inhibitions of growth factor function is Cetuximab (ErbituxTM,C225).BevacizumabIt is an example of the monoclonal antibody directly against VEGFR.Epidermal growth The example of the micromolecular inhibitor of factor acceptor includes but is not limited to LapatinibAnd Tarceva Imatinib mesylateIt is an example of PDGFR inhibitor.The example of VEGFR inhibitor includes handkerchief azoles handkerchief Buddhist nunZD6474, AZD2171, PTK787, Sutent and Sorafenib.
Anti- micro-pipe or antimitotic agent are phase specific reagent (phase specific agent), and it is in cell week The interim M phases or m period is active to the micro-pipe of tumour cell.The example of anti-micro-pipe agent includes, but are not limited to diterpene Class compound (diterpenoid) and vinca alkaloids (vinca alkaloid).
The diterpene-kind compound of natural origin is the anticancer of phase specific, and its G2/M phase in the cell cycle acts as With.It is believed that diterpene-kind compound by with the protein binding, make the 'beta '-tubulin subunit of micro-pipe stable.Then point of albumen is made Solution is suppressed, and mitosis stops, and then occurs cell death.The example of diterpene-kind compound includes, but are not limited to Japanese yew Alcohol (paclitaxel) and the like docetaxel.
Taxol, 5 β, 20- epoxies -1,2 α, 4,7 β, 10 β, 13 α-hexahydroxy Japanese yew -11- alkene -9- ketone 4,10- oxalic acid Ester 2- benzoic ethers 13- (2R, 3S)-N- benzoyl -3- phenylisoserine esters；It is a kind of purple from the short leaf of Pacific yew tree The natural diterpene product separated in China fir (Taxus brevifolia), and it is used as the solution of injectableIt is commercially available can Obtain.It is terpene taxane family member.It was separated first in 1971 by Wani et al. (J.Am.Chem, Soc.,93:2325 (1971)), and its structure is characterized by chemistry and X-ray crystallography method.One of its active mechanism is On the ability of taxol combination tubulin, thus suppress growth of cancer cells.Schiff et al.,Proc.Natl,Acad, Sci.USA,77:1561-1565(1980)；Schiff et al.,Nature,277:665-667(1979)；Kumar, J.Biol,Chem,256:10435-10441(1981).The summary of synthesis and active anticancer for some paclitaxel derivatives, Referring to: D.G.I.Kingston et al., Studies in Organic Chemistry vol.26, entitled " New trends in Natural Products Chemistry 1986”,Attaur-Rahman,P.W.Le Quesne,Eds. (Elsevier,Amsterdam,1986)pp 219-235。
In the U.S., the clinical application of taxol is had been approved by, for treating refractory ovarian (Markman et al.,Yale Journal of Biology and Medicine,64:583,1991；McGuire et al., Ann.Int.Med.,111：273,1989) and for treat breast cancer (Holmes et al., J.Nat.Cancer Inst., 83:1797,1991.).Its for it is a kind of be used to treating cutaneum carcinoma (Einzig et.al., Proc.Am.Soc.Clin.Oncol., 20：46) with head and neck cancer (Forastire et.al., Sem.Oncol., 20：56,1990) possible drug candidate.The chemical combination Thing also has treatment POLYCYSTIC KIDNEY DISEASE (Woo et.al., Nature, 368：750,1994), the potentiality of lung cancer and malaria.Using Paclitaxel treatment patient, cause bone marrow suppression (cell multiplex pedigree (multiple cell lineage), Ignoff, R.J.et.al, Cancer Chemotherapy Pocket Guide, 1998), this and the administration higher than threshold concentration (50nM) Duration is relevant (Kearns, C.M.et.al., Seminars in Oncology, 3 (6) are p.16-23,1995).
Docetaxel, (2R, 3S)-N- carboxyl -3- phenylisoserine N- tertiary butyl esters, 13- esters and 5 β -20- epoxy -1, 2 α, 4,7 β, 10 β, 13 α-hexahydroxy Japanese yew -11- alkene -9- ketone 4- acetic acid esters 2- benzoic ethers, trihydrate；WithInjectable solution is commercially available to be obtained.Docetaxel is specified for treating breast cancer.Docetaxel is taxol Semi-synthetic derivative, referring to using natural precursor, the 10- deacetylate berries extracted from the needle of European yew tree are red It is prepared by mycin III.The dose-limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids (Vinca alkaloids) is derived from the antitumor of the phase specific of periwinkle plant Agent.Vinca alkaloids is worked by specifically combining tubulin in the M phases (mitosis) of cell cycle.Cause This, the tubulin molecule being combined can not aggregate into micro-pipe.Mitosis is considered as being stopped in mid-term, and subsequent cell is dead Die.The example of vinca alkaloids includes, but are not limited to vincaleukoblastinum, vincristine and vinorelbine..
Vincaleukoblastinum (Vinblastine), vinblastine sulfate, withSolution is commercially available obtains for injection.Although its Possible as the second line treatment of various solid tumors, but it is originally designed for treatment carcinoma of testis and various lymthomas, including Hodgkin's disease；And l＆H lymthoma.Bone marrow suppression is the dose-limiting side effect of vincaleukoblastinum.
Vincristine (Vincristine), vincaleukoblastinum 22- oxos-sulfate, withInjection solution is commercially available can Obtain.Vincristine is specified for treating acute leukemia, it was found that for treating Huo Qijin and non-Hodgkin's malignant lymphoma. Alopecia and effects on neural system are the most common side effects of vincristine, and produce lesser degree of bone marrow suppression and gastrointestinal mucositis work With.
Vinorelbine, 3', 4'- bis- dehydrogenation -4'- deoxidation-C'- navelbines (norvincaleukoblastine) [R- (R*, R*) -2,3 dihydroxybutanedioic acid diester (1：2) (salt)], solution is injected with preparing vinorelbine tartrateIt is commercially available to obtain, it is semi-synthetic vinca alkaloids.Vinorelbine can as single medicament or Combined with other chemotherapeutants (such as cis-platinum), for treating various solid tumors, particularly non-small cell lung cancer, late period mammary gland Cancer and hormone-refractory prostate cancer.Bone marrow suppression is the most common dose-limiting side effect of vinorelbine.
Platinum coordination complex is the anticancer of non-phase specific, and it interacts with DNA.It is thin that platinum complex enters tumour Born of the same parents, carry out aquation, and form the crosslinking in chain between chain with DNA, cause the biological action unfavorable to tumour.Platinum is matched somebody with somebody The example of position complex compound includes but is not limited to cis-platinum and carboplatin.
Cis-platinum, cis-diammine dichloro closes platinum, withSolution is commercially available obtains for injection.Cis-platinum is initially specified and used In treatment metastatic testicular cancer and oophoroma and the carcinoma of urinary bladder in late period.The major dose-limiting side effect of cis-platinum is renal toxicity And ototoxicity, the renal toxicity can be controlled by hydration and diuresis.
Carboplatin, diamino [1,1- cyclobutane-dicarboxylic acid radical (2-)-O, O'] closes platinum, withInject solution city Selling to obtain.Carboplatin is originally designed for a line and second line treatment for advanced ovarian cancer.Bone marrow suppression is the dosage limitation of carboplatin Property toxicity.
Alkylating agent is non-phase specific anticancer agent and strong electrophilic reagent.Generally, alkylating agent is by means of alkylating, By nucleophilic moiety such as phosphate (phosphate), amino, sulfydryl, hydroxyl, carboxyl and the imidazole radicals of DNA molecular, with DNA Form covalent bond.Such alkylating destroys nucleic acid function, causes cell death.The example of alkylating agent includes, but does not limit In mustargen, such as endoxan, melphalan and Chlorambucil；Alkyl sulfonate esters, such as busulfan；Nitroso ureas, such as block Mo Siting；And triazenes, such as Dacarbazine.
Endoxan, 2- [double (2- chloroethyls) amino] tetrahydrochysene -2H-1,3,2- oxynitride phosphor heterocycle hexadienes (oxazaphosphorine) 2- oxides monohydrate, withInjection solution or tablet is commercially available obtains.Ring phosphorus Acid amides specify as single medicament or with other chemotherapeutic combinations, for treating malignant lymphoma, Huppert's disease And leukaemia.Alopecia, Nausea and vomiting and leukopenia are the most common dose-limiting side effects of endoxan.
Melphalan, 4- [double (2- chloroethyls) amino]-L- phenylalanines, withInject solution or tablet It is commercially available to obtain.Melphalan specifies the palliative treatment for Huppert's disease and unresectable epithelial ovarian cancer.Marrow presses down System is the most common dose-limiting side effect of melphalan.
Chlorambucil, 4- [double (2- chloroethyls) amino] benzenebutanoic acid, withTablet is commercially available to be obtained.Benzene Butyric acid mustargen is specified for chronic lymphocytic leukemia and malignant lymphoma (such as lymphosarcoma, giant follicular lymphoma And Hodgkin's disease) palliative treatment.Bone marrow suppression is the most common dose-limiting side effect of Chlorambucil.
Busulfan, Busulfan, withTablet is commercially available to be obtained.Busulfan, which is specified, to be used In the palliative treatment of chronic granulocytic leukemia.Bone marrow suppression is the most common dose-limiting side effect of busulfan.
BCNU, 1,3- [double (2- chloroethyls) -1- nitroso ureas, withThe lyophilized products of single bottle are commercially available to be obtained .BCNU specify as single medicament or with other pharmaceutical agent combinations, for brain tumor, Huppert's disease, Hodgkin's disease With the palliative treatment of NHL.The bone marrow suppression of delay is the most common dose-limiting side effect of BCNU..
Dacarbazine, 5- (3,3- dimethyl -1- triazenyls)-imidazoles -4- formamides, withSingle bottle is filled Material commercially available obtain.Dacarbazine specifies the treatment for metastatic malignant melanoma, and can with other pharmaceutical agent combinations, Second line treatment for Hodgkin's disease.Nausea and vomiting and apocleisis are the most common dose-limiting side effects of Dacarbazine.
Antibioticses antitumor agent (Antibiotic anti-neoplastics) is the medicament of non-phase specific, its With reference to or the intercalation of DNA in.Generally, this effect causes DNA compounds or the chain fracture of stabilization, destroys the normal function of nucleic acid, Cause cell death.The example of antibioticses antitumor agent includes but is not limited to D actinomycin D (such as dactinomycin D), anthracycline (anthrocyclins) (such as daunorubicin and Doxorubicin)；And bleomycin.
Dactinomycin D, also referred to as actinomycin D, withParenteral solution form is commercially available to be obtained.Dactinomycin D Specify the treatment for wilms' tumor (Wilm ' s tumor) and rhabdomyosarcoma.Nausea and vomiting and apocleisis are more to mildew The most common dose-limiting side effect of element.
Daunorubicin, (8S- cis -) -8- acetyl group -10- [(3- amino -2,3, the deoxy α-L- lysols of 6- tri--own pyrrole Mutter glycosyl)-epoxide] -7,8,9,10- tetrahydrochysenes -6,8,11- trihydroxy -1- methoxyl group -5,12- aphthacene dione hydrochlorides, withLiposome injectable forms orInjectable forms are commercially available to be obtained.Daunorubicin refers to Being scheduled in the treatment of the acute nonlymphocytic leukemia Kaposi sarcoma related to late period HIV is used for induction of remission. Bone marrow suppression is the most common dose-limiting side effect of daunorubicin.
Doxorubicin, (8S, 10S) -10- [(3- amino -2,3, the deoxidation-α-L- lysols of 6- tri--own pyranose) epoxide] - 8- glycolyls -7,8,9,10- tetrahydrochysenes -6,8,11- trihydroxy -1- methoxyl group -5,12- aphthacene dione hydrochlorides, withOr ADRIAMYCINSolution is commercially available obtains for injection.Doxorubicin is originally designed for acute thin into lymph The treatment of born of the same parents' property leukaemia and acute myeloblastic leukemia, but be also useful group of some solid tumors for the treatment of and lymthoma Point.Bone marrow suppression is the most common dose-limiting side effect of Doxorubicin..
Bleomycin, is the cell separated from streptomyces verticillus (streptomyces verticilus) bacterial strain The mixture of toxin glycopeptide antibiotics, withIt is commercially available to obtain.Bleomycin as single medicament or with Other pharmaceutical agent combinations, the palliative treatment for squamous cell carcinoma, lymthoma and carcinoma of testis.Lung and dermal toxicity are bleomycins Most common dose-limiting side effect.
Topoisomerase II inhibitors include but is not limited to table Podophyllum emodi var chinense lipoxin.
Table Podophyllum emodi var chinense lipoxin is derived from the antineoplastic of the phase specific of mandrake (mandrake) plant.Table Podophyllum emodi var chinense lipoxin with topoisomerase II and DNA generally by forming ternary complex, to influence S and G2 in the cell cycle The cell of phase, causes DNA fracture.Chain fracture accumulation, then cell death.The example of table Podophyllum emodi var chinense lipoxin includes but not limited In Etoposide and Teniposide.
Etoposide, 4'- demethyls-table Podophyllum emodi var chinense lipoxin 9 [4,6-0- (R)-ethylidene-β-D- glucopyranosides], WithInjection solution or capsule is commercially available obtains, and commonly referred to as VP-16.Etoposide is specified as single Medicament or with other chemotherapeutic agent combinations, for treating carcinoma of testis and non-small cell lung cancer.Bone marrow suppression is that Etoposide is most common Side effect.The incidence of disease of leukopenia tends to more serious than the incidence of disease of thrombopenia..
Teniposide, 4'- demethyls-table Podophyllum emodi var chinense lipoxin 9 [4,6-0- (R)-thenylidene-β-D- glucopyranoses Glycosides], withSolution is commercially available obtains for injection, and commonly referred to as VM-26.Teniposide is specified and is used as single medicine Agent or with other chemotherapeutic agent combinations, for treating acute leukemia.Bone marrow suppression is the most common dosage limit of Teniposide Property side effect processed.Teniposide can cause leukopenia and thrombopenia.
Antimetabolic oncology pharmacy is the anti-tumor agents of phase specific, and its S phase for acting on the cell cycle, (DNA was closed Into), by suppressing DNA synthesis, or by suppressing the synthesis of purine or pyrimidine bases so as to limit DNA synthesis.Therefore, The S phases can not continue, then cell death.The example of anti-metabolism anti-tumor agents includes, but are not limited to fluorouracil, first Aminopterin, cytarabine, purinethol, thioguanine and gemcitabine.
5 FU 5 fluorouracil, 5- fluoro- 2,4- (1H, 3H) hybar X, is obtained so that fluorouracil is commercially available.5 FU 5 fluorouracil Administration causes the suppression that thymidylic acid is synthesized, and is also coupled in RNA and DNA.As a result it is typically cell death.5 FU 5 fluorouracil Specify as single medicament or with other chemotherapeutic agent combinations, for treating breast cancer, colon and rectum carcinoma, stomach cancer and pancreas Cancer.Bone marrow suppression and catarrh are the dose-limiting side effects of 5 FU 5 fluorouracil.Other fluoropyrimidine analogues include 5- fluorine Deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphates.
Cytarabine, (the 1H)-pyrimidone of 4- amino -1- β-D- arabinofuranosidases glycosyl -2, withIt is commercially available It can obtain, and normally referred to as Ara-C.It is believed that cytarabine has cell phase specificity in the S- phases, it is by by arabinose Cytidine end is attached in the DNA of growth and suppressed the extension of DNA.Cytarabine as single medicament or with otherization Agent combination is treated, for treating acute leukemia.Other cytidine analogs include 5-azacitidine and 2', 2'- difluoro deoxidation born of the same parents Glycosides (gemcitabine).Cytarabine causes leukopenia, thrombopenia and catarrh.
Purinethol, 1,7- dihydro -6H- purine -6- thioketones monohydrates, withIt is commercially available to obtain. Purinethol suppresses DNA synthesis in the S- phases by not yet clear mechanism so far, shows cell phase specificity.Sulfydryl is fast Purine specify as single medicament or with other chemotherapeutic agent combinations, for treating acute leukemia.It is expected that bone marrow suppression and stomach and intestine Catarrh is the side effect of high dose purinethol.Workable purinethol analog is imuran..
Thioguanine, 2- amino -1,7- dihydro -6H- purine -6- thioketones, withIt is commercially available to obtain.Sulphur bird is fast Purine suppresses DNA synthesis in the S- phases by not yet clear mechanism so far, shows cell phase specificity.Thioguanine is specified As single medicament or with other chemotherapeutic agent combinations, for treating acute leukemia.Bone marrow suppression, including Neuroleptic Leukocytopenia Disease, thrombopenia and anaemia are the administration most common dose-limiting side effects of thioguanine.However, also occurring stomach and intestine pair Effect, and the side effect is probably dose-limiting.Other purine analogues include Pentostatin, erythro form hydroxynonyl Adenine (erythrohydroxynonyladenine), fludarabine phosphate and Cladribine.
Gemcitabine, the hydrochloride (β-isomers) of 2'- deoxidations -2', 2'- difluoro cytidine one, withIt is commercially available to obtain .Gemcitabine by block cell by the development on G1/S borders shown in the S- phases cell phase specificity.Gemcitabine Specify and cisplatin combination, the local advanced Non-small cell lung for treating, and be individually used for the local advanced pancreatic cancer for the treatment of. Bone marrow suppression (including leukopenia, thrombopenia and anaemia) is that administration gemcitabine is most common dose-limiting Side effect.
Methotrexate (MTX), N- [4 [[(2,4- diaminourea -6- pteridyls) methyl] methylamino] benzoyl]-Pidolidone, Obtained so that methotrexate sodium is commercially available.Methotrexate (MTX) shows cell phase specific effect in the S- phases, and it is synthesized by suppressing Dehydrofolic acid reductase needed for purine nucleotides and thymidylic acid suppressing DNA synthesis, repair and/or replicate.Methotrexate (MTX) Specify as single medicament or with other chemotherapeutic agent combinations, for treating choriocarcinoma, meningeal leukemia, non-Hodgkin's lymph Knurl, and breast cancer, head cancer, neck cancer, oophoroma and carcinoma of urinary bladder.It is expected that bone marrow suppression (leukopenia, thrombopenia And anaemia) and catarrh be administered methotrexate (MTX) side effect.
Camptothecine (Camptothecins), including camptothecine and camptothecin derivative, are used as topoisomerase I inhibitor To use or under development.Camptothecine cytotoxic activity is considered as related to its topoisomerase I inhibitory activity.Camptothecine Example includes, but are not limited to Irinotecan, Hycamtin, and 7- (4- methyl piperazines base-methylene) -10,11- as described below The various optical forms of ethylenedioxy-CPT.
Irinotecan hydrochloride (Irinotecan HCl), (4S) -4,11- diethyl -4- hydroxyls -9- [(4- piperidinyl piperidines Base) carbonyl epoxide] -1H- pyrans simultaneously [3', 4', 6,7] indolizino [1,2-b] quinoline -3,14 (4H, 12H)-dione hydrochloride, WithSolution is commercially available obtains for injection.
Irinotecan is the derivative of camptothecine, and it combines topoisomerase I-DNA together with its active metabolite SN-38 Compound.It is believed that double-strand unrepairable (irreparable) fracture, cause cytotoxicity occur, the fracture be by Topoisomerase I：DNA：Caused by interaction between Irinotecan or SN-38 ternary complexs and replicase.Yi Li is replaced Kang Zhiding is used for the metastatic carcinoma for treating colon or rectum.The dose-limiting side effect of irinotecan hydrochloride is bone marrow suppression, bag Include neutropenia, and the GI effects including diarrhoea.
Hydrochloric acid Hycamtin (Topotecan HCl), (S) -10- [(dimethylamino) methyl] -4- ethyl -4,9- dihydroxies Base -1H- pyrans simultaneously [3', 4', 6,7] indolizino [1,2-b] quinoline -3,14- (4H, 12H)-hydrochloride of diketone one, withSolution is commercially available obtains for injection.Hycamtin is the derivative of camptothecine, and it is multiple with topoisomerase I-DNA Compound is combined, and prevents the reconnection of single-strand break, and the single-strand break is that the torsion of topoisomerase I response DNA molecular should Caused by power (torsional strain).Hycamtin is specified to be controlled for the two wires of Metastatic carcinoma in the ovary and ED-SCLC Treat.The dose-limiting side effect of hydrochloric acid Hycamtin is bone marrow suppression, mainly neutropenia.
The preparation of compound
General synthetic scheme
The compound of the present invention can be prepared by a variety of methods, including well known Standard synthetic methods.It is following to list Exemplary universal synthesis method, is then prepared for the specific compound of the present invention in embodiment.Those skilled in the art should Work as understanding, can be with for stable reaction conditions if substituent described herein is incompatible with synthetic method described herein Suitable protection group protect the substituent.Removal protection group can be suitably put in reaction sequence, desired centre is obtained Body or target compound.In all schemes as described below, when the rule according to synthesis chemistry is required, using for Protection group (the T.W.Green and P.G.M.Wuts, (1991) Protecting Groups of sensitive group or reactive group In OrganicSynthesis, John Wiley＆Sons, are incorporated by reference into the content wherein on protection group).In chemical combination What thing was synthesized facilitates the stage, and these groups are removed using for the method that those skilled in the art are readily apparent.Work The selection of skill and reaction condition and their implementation order should be consistent with preparing for the compound of the present invention.
The compound of logical formula (I) and its synthesis of pharmaceutically acceptable derivative and salt can be pressed by those skilled in the art According to realization listed in following scheme 1-5.In following description, unless otherwise stated, each group is as described above for formula (I) what compound was defined.Parent material is commercially available obtainable, or using method known to those skilled in the art by commercially available It is prepared by obtainable parent material.
The compound of formula (II) can be prepared as shown in scheme 1.Under palladium coupling conditions, such as using PdCl2(dppf) And Cs2CO3, the aryl bromourea intermediate A properly replaced can be coupled with borate intermediate B, obtain intermediate C.To methoxyl group The deprotection of benzyl (PMB) or benzyl (Bn) part can be in H2Under atmosphere or in acid condition (such as using TFA or HCl) Realized in the presence of palladium carbon, obtain formula (II) compound.
Scheme 1
Intermediate C can also be prepared such as the example of scheme 2.Under palladium coupling conditions, such as using PdCl2(dppf) and Cs2CO3, pyridine radicals (or pyrimidine radicals) the bromide intermediate D properly replaced can be even with boric acid (or borate) urea intermediate E Close, obtain intermediate C.Similar to the condition in scheme 1, intermediate C can be further converted into formula (II) compound.Can Selection of land, according to the method for scheme 2, by using unprotected intermediate D variant, can directly prepare the chemical combination of formula (II) Thing.
Scheme 2
Intermediate C can also be prepared such as the example of scheme 3.Under suitable conditions, such as using PdCl2(dppf) and Cs2CO3, aryl bromide F can be coupled with borate intermediate B, obtain intermediate G, and then it can be with the isocyanic acid that properly replaces Ester is coupled, and obtains urea intermediate C.Alternatively, using suitable reagent such as triphosgene, intermediate G can be changed into isocyanide Acid esters, then with the amine coupling properly replaced, obtains urea intermediate C.Similar to the condition in scheme 1, intermediate C can be entered The compound of an one step conversion accepted way of doing sth (II).
Scheme 3
Intermediate C can also be prepared such as the example of scheme 4.Using suitable reagent such as DPPA, will can properly it replace Sour H changes into isocyanates, then with the amine coupling properly replaced, obtains urea intermediate C., can similar to the condition in scheme 1 So that intermediate C to be further converted into formula (II) compound.
Scheme 4
The compound of formula (III) can be prepared such as the example of scheme 5.The pyridone I properly replaced can be with nitro compound Thing J is coupled, and obtains ether, then under suitable conditions, such as, using zinc in methyl alcohol, it can be reduced, and obtain aniline Intermediate K.Intermediate K can be coupled with the isocyanates properly replaced, or be changed into suitable reagent such as triphosgene Isocyanates, then with the amine coupling properly replaced, obtains urea intermediate L.To methoxy-benzyl (PMB) or benzyl (Bn) part Deprotection can be in H2Realize, obtain in the presence of palladium carbon under atmosphere or in acid condition (such as using TFA or HCl) The compound of formula (III).
Scheme 5
Test example
Following embodiment explanation present invention.These embodiments are not intended to limit the scope of the present invention, but are this area Technical staff is provided on preparing and using the guidance of the compound of the present invention, composition and method.Although describing the present invention Specific embodiment, it should be appreciated to those skilled in the art that in the situation without departing substantially from the spirit and scope of the present invention Under, can be so that various changes and modifications can be made.Unless otherwise stated, reagent is the commercially available obtainable or side in document Prepared by method.The symbol and convention and contemporary scientific literature such as the used in description method, scheme and embodiment Journal of the American Chemical Society or the Journal of Biological Chemistry Those middle used are consistent.
In embodiment:
Chemical shift is represented with PPM (ppm) unit.The unit of coupling constant (J) is hertz (Hz).Split-mode Formula describes apparent multiplicity (apparent multiplicities), and it is (triple to be referred to as s (unimodal), d (bimodal), t Peak), q (quartet), dd (double doublet), dt (double triplets), dq (double quartets), m (multiplet), br (broad peak).
Flash column chromatography is carried out on silica gel.
Used naming program is ACDLABs 11.0 Namebatch, ACD IUPAC, or Ultra。
Abbreviation
Ac2O acetic anhydrides
AcOH acetic acid
BH3DMS borine dimethyl sulfide complex
BH3THF borine tetrahydrofuran compounds
Bn benzyls
Boc2The carbonic ester of O di-t-butyls two
CDCl3Chloroform-d
CD3OD methanol-d4
Cs2CO3Cesium carbonate
DAST diethylaminosulfurtrifluorides
DCM dichloromethane
DIBAl-H diisobutyl aluminium hydrides
DIEA diisopropylethylamine
DMAP 4-dimethylaminopyridines
DMF N,N-dimethylformamides
DMSO-d6Dimethyl sulfoxide-d6
DPPA diphenyl phosphoryl azides
EA ethyl acetate
EDC 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide
ES-LCMS electron spray liquid chromatography-mass spectrographies
EtI iodoethane
Et3N triethylamines
EtOH ethanol
G grams
H hours
H2Hydrogen
HATU O- (7- azepine benzos triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluoro phosphorus Acid esters
HBr hydrogen bromides
HCl hydrochloric acid
H2O water
H2O2Hydrogen peroxide
HOBt hydroxybenzotriazoles
HPLC high performance liquid chromatography
H3PO2Phosphinic acids
H2SO4Sulfuric acid
In vacuo are under vacuo
K2CO3Potassium carbonate
KOAc potassium acetates
KOH potassium hydroxide
LAH lithium aluminium hydride reductions
LCMS liquid chromatography-mass spectrographies
LiOH lithium hydroxides
LiOH·H2O lithium hydroxide monohydrates
The m- chloroperoxybenzoic acids of m-CPBA
MeCN acetonitriles
MeI iodomethanes
MeMgBr methylmagnesium-bromides
MeOH methanol
Mg milligrams
MgSO4Magnesium sulfate
Min minutes
ML milliliters
Mmol mMs
N2Nitrogen
NaBH4Sodium borohydride
NaBH(OAc)3Sodium triacetoxy borohydride
Na2CO3Sodium carbonate
NaH sodium hydrides
NaHCO3Sodium acid carbonate
NaI sodium iodides
NaIO4Sodium metaperiodate
NaNO2Natrium nitrosum
NaOEt caustic alcohols
NaOH sodium hydroxides
Na2SO4Sodium sulphate
NBS N-bromosuccinimides
N-BuLi n-BuLis
NH4Cl ammonium chlorides
(NH4)HCO3Ammonium hydrogen carbonate
NH4OAc ammonium acetates
NH4OH ammonium hydroxide
NIS N- iodine succinimides
NMR nuclear magnetic resonance
Pd/C palladium carbons
PdCl2(dppf) double (diphenyl phosphine) ferrocene of 1,1'-] dichloro palladium (II)
PdCl2(PPh3)2Double (triphenylphosphine) ferrocene] dichloro palladium (II)
Pd2(dba)3The double palladiums (0) of three (double BENZYLIDENE ACETONEs)
PE petroleum ethers
The p- methoxy-benzyls of PMB
POCl3POCl3
Rt room temperatures
SnCl2·H2O stannic chlorides (II) hydrate
SOCl2Thionyl chloride
TBME t-butyl methyl ethers
TBS t-butyldimethylsilyls
TBSCl tert-butyldimethylsilyl chlorides
TFA trifluoroacetic acids
TFAA TFAAs
THF tetrahydrofurans
TLC thin-layer chromatographys
The preparation of intermediate
Intermediate 1：3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxies Miscellaneous boron heterocycle pentane (dioxaborolan) -2- bases) pyridine
Step 1：The bromo- 5- ethoxy pyridines of 3-
At 25 DEG C, stirring 5- bromopyridine -3- alcohol (70g, 402mmol), K2CO3(111g, 805mmol) and EtI The solution of (69.0g, 443mmol) in DMF (700mL) 16 hours.Then, the mixture is concentrated, is diluted with water, with DCM (2 × 200mL) extraction, through Na2SO4It is dried and concentrated, obtains the bromo- 5- ethyoxyls pyrroles of 3- (53g, 218mmol, yield 54.2%)：1H NMR(400MHz,CD3OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40 (t, J= 7.0Hz,3H)；ES-LCMS m/z 202(M+H).
Step 2：The bromo- 5- ethoxy pyridines 1- oxides of 3-
Through 30 minutes, to solution of the bromo- 5- ethoxy pyridines (53g, 262mmol) of 3- in DCM (200mL) at 0 DEG C In be slowly added m-CPBA (67.9g, 393mmol).After the solution that stirring is obtained 15 hours, the mixture is used NaS2O3Solution is washed, and is extracted with DCM (2 × 300mL), through Na2SO4Dry, and concentrate organic phase, obtain the bromo- 5- ethoxies of 3- Yl pyridines 1- oxides (40g, 165mmol, 62.9%yield):1H NMR(400MHz,CD3OD)δ8.19-8.18(m,1H), 8.08-8.07 (m, 1H), 7.50-7.49 (m, 1H), 4.17-4.15 (d, J=8.8Hz, 2H), 1.43 (t, J=7.0Hz, 3H)； ES-LCMS m/z 217(M+H)。
Step 3：The bromo- 2- chloro-3-ethoxies pyridines of 5-
Through 30 minutes, at 0 DEG C the bromo- 5- ethoxy pyridines 1- oxides (40g, 183mmol) of 3- at DCM (200mL) In solution in be slowly added POCl3(159mL,1701mmol).Then, so as to get solution be warming up to 45 DEG C 15 hours. The mixture is concentrated, and is extracted with DCM (2 × 200mL), through Na2SO4It is dried and concentrated, obtains the bromo- 2- chloro-3-ethoxies pyrroles of 5- Pyridine (30g, 60.9mmol, yield 33.2%)：1H NMR(400MHz,CD3OD) δ 8.00-7.99 (d, J=2.0Hz, 1H), 7.65-7.64 (d, J=2.0Hz, 1H), 4.17-4.12 (m, 2H), 1.44 (t, J=7.0Hz, 2H)；ES-LCMS m/z 235 (M+H)。
Step 4：The bromo- 3- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine
At 0 DEG C, into mixture of (4- methoxyphenyls) methanol (16.71g, 121mmol) in DMF (200mL) Add NaH (3.96g, 165mmol).After the mixture is stirred 30 minutes, the bromo- 2- of 5- are added into said mixture chloro- 3- ethoxy pyridines (26g, 110mmol), and at 80-90 DEG C, stir the mixture 12 hours.Use H2This is quenched in O (20mL) Mixture, is extracted with DCM (2 × 200mL), through Na2SO4Dry, filter, concentration, and via column chromatography (10%EA/90%PE, 360g silicagel columns) purifying.Merga pass TLC (EA/PE=5:1,Rf=0.5) find to include all fractions of product, and concentrate, Obtain the bromo- 3- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (36g, 74.5mmol, yield of white solid 67.8%)：1H NMR(400MHz,CD3OD) δ 7.71 (d, J=2.0Hz, 1H), 7.36-7.31 (m, 3H), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H), 2.37 (d, J=7.0Hz, 3H)；ES-LCMS m/z 338 (M+H)。
Step 5：3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxas Boron heterocycle pentane -2- bases) pyridine
At 20 DEG C, in N2Under, to the bromo- 3- ethyoxyls -2- of the 5- of stirring ((4- methoxy-benzyls) epoxide) pyridine (10g, 29.6mmol), 4,4,4', 4', 5,5,5', 5'- prestox -2,2'- double (1,3,2- dioxaborolans alkane) (8.26g, 32.5mmol) and in solution of the KOAc (7.25g, 73.9mmol) in 1,4- dioxanes (250mL) disposably add PdCl2 (dppf)(1.082g,1.478mmol).At 100 DEG C, stirring reaction mixture 3 hours.The mixture is filtered, and in vacuum Middle concentration filtrate, then passes through silica gel column chromatography (PE/EA=10:1) purify.Merga pass TLC (PE/EA=10:1,Rf= 0.6) all fractions for including product are found, and are concentrated, 3- ethyoxyls -2- ((4- methoxy-benzyls) oxygen of white solid is obtained Base) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (9.2g, 23.88mmol, yield 81.0%)：1H NMR(400MHz,CDCl3) δ 8.10 (s, 1H), 7.42 (d, J=8.8Hz, 2H), 7.33 (s, 1H), 6.88- 6.85 (m, 2H), 5.45 (s, 2H), 4.11-4.06 (m, 2H), 3.78 (s, 3H), 1.43 (t, J=7.0Hz, 3H), 1.33 (s, 12H)；ES-LCMS m/z 386.0(M+H).
Intermediate 2：4- (4- ethyl-piperazin -1- ylmethyls) -3- trifluoromethyl-anilines
Step 1：(4- amino -2- trifluoromethyl-phenyls)-(4- ethyl-piperazin -1- bases)-ketone
At 25 DEG C, stirring 4- amino -2- Trifluoromethyl-benzoic acids (15g, 73.1mmol), HOBT (14.56g, 95mmol)、EDC(16.82g,88mmol)、Et3N (20.38mL, 146mmol), 1- ethyl-piperazins (8.35g, 73.1mmol) Mixture in DCM (200mL) 2 hours.DCM (200mL) is added into the mixture, H is then used2O、2mol/L NaOH (2 × 150mL) and salt water washing.Through Na2SO4Dry organic layer and concentrate, obtain (4- amino -2- the fluoroforms of white-yellowish solid Base-phenyl)-(4- ethyl-piperazin -1- bases)-ketone (20g, 65.2mmol, yield 89.0%)：1H NMR(400MHz,CDCl3) δ 7.07 (d, J=8.0Hz, 1H), 6.92 (d, J=2.4Hz, 1H), 6.79 (dd, J=2.0,8.0Hz, 1H), 3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H), 2.33-2.31 (m, 2H), 1.08 (t, J= 7.2Hz,3H)；ES-LCMS m/z 302(M+H).
Step 2：4- (4- ethyl-piperazin -1- ylmethyls) -3- trifluoromethyl-anilines
To (4- amino -2- trifluoromethyl-phenyls)-(4- ethyl-piperazin -1- bases)-ketone (20g, 66.4mmol) in THF BH is added dropwise in mixture in (500mL)3·DMS(19.91mL,199mmol).Then, the mixture 4 is stirred at 80 DEG C small When.The mixture is quenched by adding MeOH, then concentrates.Pass through the silica gel column chromatography (PE on silica gel:EA=2：1, Rf= 0.35) purify residue, obtain white solid 4- (4- ethyl-piperazin -1- ylmethyls) -3- trifluoromethyl-anilines (14g, 46.0mmol, yield 69.4%)：1H NMR(400MHz,CDCl3) δ 7.48 (d, J=8.4Hz, 1H), 6.91 (d, J=2.8Hz, 1H), 6.79 (dd, J=2.4,8.4Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J= 7.2Hz,3H)；ES-LCMS m/z 288(M+H).
Intermediate 3：4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) aniline
Step 1：3- methy oxetane -3- alcohol
It is added dropwise to being cooled in mixture of 0 DEG C of the oxetanes -3- ketone (8g, 111mmol) in THF (300mL) MeMgBr(74.0mL,222mmol).At 25 DEG C, the mixture is stirred 2 hours.Use NH4The mixture is quenched in Cl (aq.).Cross Sediment is filtered, and is washed with DCM.Concentrate filtrate, obtain light yellow oil 3- methy oxetane -3- alcohol (7.5g, 85mmol, yield 77%)：1H NMR(400MHz,CDCl3) δ 4.61 (d, J=6.4Hz, 2H), 4.46 (d, J=7.2Hz, 2H), 2.31(s,1H),1.56(s,3H)。
Step 2：3- methyl -3- (4- nitros -2- (trifluoromethyl) phenoxy group) oxetanes
To fluoro- 4- nitros -2- (trifluoromethyl) benzene (10g, 47.8mmol) of 1- and 3- methy oxetane -3- alcohol Cs is added in the mixture of (3.51mL, 47.8mmol) in MeCN (100mL)2CO3(46.7g,143mmol).At 80 DEG C, Stir the mixture 10 hours.Filter the mixture.Filtrate is concentrated, and passes through silica gel column chromatography (PE/EA=20:1) purify residual Excess.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain pale yellow 3- methyl -3- (4- nitros -2- (trifluoromethyl) phenoxy group) oxetanes (10g, 35.8mmol, yield of color solid 74.8%):1H NMR(400MHz,CDCl3) δ 8.54 (d, J=2.8Hz, 1H), 8.36 (dd, J=2.8,9.2Hz, 1H), 6.50 (d, J=9.2Hz, 1H), 4.98 (d, J=6.8Hz, 2H), 4.67 (d, J=7.6Hz, 2H), 1.84 (s, 3H)；ES-LCMS m/ z 278(M+H)。
Step 3：4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) aniline
At 40 DEG C, in H2Under atmosphere (50psi), 3- methyl -3- (4- nitros -2- (trifluoromethyl) phenoxy group) oxygen is hydrogenated Azetidine (10g, 36.1mmol) and Pd/C (0.384g, 3.61mmol；10%) reactant mixture in MeOH (50mL) 20 hours.The mixture is concentrated, 4- ((3- methy oxetane -3- bases) epoxide) -3- (fluoroforms of brown oil are obtained Base) aniline (8.5g, 34.1mmol, yield 95%)：1H NMR(400MHz,CDCl3) δ 6.92 (d, J=2.8Hz, 1H), 6.72 (dd, J=2.8,8.8Hz, 1H), 6.35 (d, J=8.4Hz, 1H), 4.95 (d, J=6.4Hz, 2H), 4.52 (d, J=7.2Hz, 2H),3.60(s,2H),1.68(s,3H)；ES-LCMS m/z 248(M+H).
Intermediate 4：1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) - 3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline
To the bromo- 2- fluoroanilines (40g, 211mmol) of the 4- stirred at 20 DEG C, 4,4,4', 4', 5,5,5', the first of 5'- eight Base -2,2'- double (1,3,2- dioxaborolans alkane) (64.1g, 253mmol) and KOAc (41.3g, 421mmol) are in 1,4- It is disposable in solution in dioxane (500mL) to add PdCl2(dppf)(7.70g,10.53mmol).Stirred at 100 DEG C anti- Answer mixture 3 hours.Solution is concentrated under vacuum, the fluoro- 4- of 2- (4,4,5,5- tetramethyls -1,3,2- dioxa boron heterocycles are obtained Pentane -2- bases) aniline (44g, 158mmol, yield 74.9%)：1H NMR(400MHz,CDCl3)δ7.46-7.40(m,2H), 6.75-6.71 (m, 1H), 1.30 (s, J=3.6Hz, 12H)；ES-LCMS m/z 238.1(M+H).
Step 2：2- (fluoro- 4- isocyanatos (isocyanato) phenyl of 3-) -4,4,5,5- tetramethyl -1,3,2- dioxas Boron heterocycle pentane (dioxaborolane)
To the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline (500mg, Triphosgene (250mg, 0.844mmol) 2.109mmol) is added in the mixture in THF (10mL).At 60 DEG C, stirring should Mixture 30 minutes.Evaporation residue, obtains 2- (the fluoro- 4- isocyanatophenyls of 3-) -4,4,5,5- tetramethyls -1,3,2- dioxies Miscellaneous boron heterocycle pentane (500mg, 1.616mmol, yield 77%)；ES-LCMS m/z 296.1(M+MeOH+H).
Step 3：1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 2- (the fluoro- 4- isocyanatophenyls of 3-) -4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane In the mixture of (500mg, 1.901mmol) in THF (10mL) add 4- ((3- methy oxetane -3- bases) epoxide) - 3- (trifluoromethyl) aniline (517mg, 2.091mmol) and Et3N(0.530mL,3.80mmol).At 60 DEG C, the mixing is stirred Thing 1 hour.The mixture is concentrated, and by preparing TLC (PE/EA=3:1,Rf=0.6) purify, obtain light yellow solid 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (500mg, 0.980mmol, yield 51.6%)：1H NMR (400MHz,CDCl3) δ 8.15 (t, J=8.0Hz, 1H), 7.77-7.76 (d J=2.8Hz, 1H), 7.55-7.52 (m, 1H), 7.49-7.47 (m, 1H), 7.42-7.38 (m, 1H), 6.62-6.60 (d, J=8.8Hz, 1H), 4.91-4.89 (d, J= 6.0Hz, 2H), 4.63-4.61 (d, J=7.6Hz, 2H), 1.71 (s, 3H), 1.33 (s, 12H)；ES-LCMS m/z 511.2(M +H)。
Intermediate 5：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylics Acid
Step 1：6- methyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters
Stir urea (50g, 833mmol), ethyl 3-oxobutanoate (119g, 916mmol) acton (136g, Solution in 916mmol) 28 hours, while in N2Under atmosphere, EtOH is distilled out at 80 DEG C.Then, the mixture is cooled down To 20 DEG C, and add EtOH (800mL), the NaOEt added into said mixture in EtOH (500mL) (85g, 1249mmol), and at 80 DEG C stir the mixture 2 hours, the mixture be cooled to 20 DEG C, be subsequently added into water (400mL), AcOH (60mL) is added at 20-30 DEG C, the mixture is then filtered, washs solid with water (200mL), dry, obtain afterwards 6- methyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (70g, 384mmol, yield 46.2%).1H NMR(400MHz, DMSO-d6) δ 8.81 (s, 1H), 4.31 (q, J=7.2Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.2Hz, 3H)；LCMS m/z 183.2(M+H).
Step 2：The chloro- 4- methylpyrimidines -5- carboxylic acid, ethyl esters of 2-
To at 20 DEG C, in N2Lower stirring 6- methyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (62g, POCl is slowly added in solution 340mmol)3(496g,3233mmol).At 80 DEG C, stirring reaction mixture 12 hours. Then, the solution is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution.The organic extract of merging is washed with salt Wash, through Na2SO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified.TLC (PE/ will be passed through EA=10:1,Rf=0.7) find that all fractions comprising product all merge, and concentrate, obtain the chloro- 4- first of 2- of yellow solid Yl pyrimidines -5- carboxylic acid, ethyl esters (9g, 44.9mmol, yield 13.18%)：1H NMR(400MHz,CDCl3)δ9.01(s,1H), 4.41 (q, J=7.2Hz, 2H), 2.82 (s, 3H), 1.41 (t, J=7.2Hz, 3H).
Step 3：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Ethyl ester
To at 20 DEG C, in N2Stirred under atmosphere 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5, 5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (6.34g, 16.45mmol), the chloro- 4- methylpyrimidines -5- of 2- Carboxylic acid, ethyl ester (3g, 14.95mmol) and Cs2CO3(9.74g, 29.9mmol) is in 1,4- dioxanes (20mL) and water (6.67mL) Solution in disposable add PdCl2(dppf)(0.547g,0.748mmol).At 110 DEG C, heating response container 2 hours. Then, the solution is concentrated, and is distributed between EA and water.By the organic extract of merging salt water washing, through MgSO4Dry, Filter and concentrate.Pass through silica gel column chromatography (PE/EA=10:1,5:1) residue is purified.TLC (PE/EA=5 will be passed through:1,Rf =0.5) find that all fractions comprising product merge, and concentrate, obtain 2- (5- ethyoxyls -6- ((the 4- first of light yellow solid Oxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acid, ethyl esters (6g, 14.17mmol, yield 95%)：1H NMR (400MHz,CDCl3) δ 9.15 (s, 1H), 8.90 (s, 1H), 8.10 (m, 1H), 7.45 (d, J=8.8Hz, 2H), 6.89 (d, J =8.8Hz, 2H), 5.50 (s, 2H), 4.45-4.37 (m, 2H), 4.20-4.15 (m, 2H), 3.80 (s, 3H), 2.90-2.81 (m, 3H), 1.48 (t, J=6.8Hz, 3H), 1.42 (t, J=7.2Hz, 3H)；LCMS m/z 424.1(M+H).
Step 4：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids
To at 20 DEG C, in N2The 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - It is disposable in solution of the 4- methylpyrimidine -5- carboxylic acid, ethyl esters (6g, 14.17mmol) in THF (20mL) to add LiOHH2O (11.34mL,28.3mmol).At 60 DEG C, the reactant mixture is stirred 12 hours.Then, the solution is concentrated, and with dense HCl is neutralized to pH=7.0, stirs simultaneously.Then, filtering solution, and wash filter cake with water (10mL).Filter is dried in a vacuum Cake, obtains 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- of white-yellowish solid Carboxylic acid (4g, 10.12mmol, yield 71.4%)：1H NMR(400MHz,CD3OD)δ8.89(s,1H),8.73(s,1H),8.12 (d, J=1.6Hz, 1H), 7.40 (d, J=8.8Hz, 2H), 6.91 (d, J=8.8Hz, 2H), 5.39 (s, 2H), 4.16 (q, J= 6.8Hz, 2H), 3.78 (s, 3H), 2.76 (s, 3H), 1.43 (t, J=6.8Hz, 3H)；LCMS m/z 396.1(M+H).
Intermediate 6:2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylics Acid
Step 1：The chloro- 4- ethoxy pyridines of 2-
At 0 DEG C, add at leisure into mixture of the chloro- 4- nitropyridines (170g, 1070mmol) of 2- in THF (2L) Enter NaOEt (109.45g, 1610mmol).At 25 DEG C, the mixture is stirred 12 hours.LCMS and TLC (PE/EA=5:1,Rf =0.6) display reaction completion.The mixture is filtered, and removes the solvent of most of filtrate in a vacuum.With EA (800mL × 3) Extracted residues, and organic layer is washed with the NaCl solution (1L) of saturation, through Na2SO4It is dried and concentrated, obtains the 2- in solid Chloro- 4- ethoxy pyridines (157g, 1.0mol, yield 92%)：1H NMR(400MHz,CD3OD) δ 8.15 (d, J=6.0Hz, 1H), 6.99 (d, J=2.0Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H)；ES- LCMS m/z 158(M+H)。
Step 2：The chloro- 4- ethoxy pyridines of the bromo- 2- of 5-
The chloro- 4- ethoxy pyridines (100g, 0.63mol) of solid 2- are slowly added to H2SO4In (500mL).Then, At room temperature, 1- bromine pyrrolidines -2,5- diketone (124.2g, 0.70mol) is added in said mixture.At 80 DEG C, stir Mix the mixture 3 hours.TLC (PE/EA=10:1, Rf=0.5) display reaction completion.Reactant mixture is poured into ice-water In (2L), and extracted with EA (1L × 3).By the Na of organic layer saturation2CO3Solution (1L × 2) is washed, through Na2SO4Dry simultaneously Concentration.In silica gel column chromatography (PE/EA=60:1-30:1) residue is purified.TLC (PE/EA=10 will be passed through:1,Rf=0.5) It was found that all fractions comprising product merge, and concentrate, obtain the chloro- 4- ethoxy pyridines of the bromo- 2- of 5- (60.9g, 0.26mol, production Rate 40%)：1H NMR(400MHz,CD3OD)δ8.31(s,1H),7.14(s,1H),4.32-4.10(m,2H),1.58-1.35 (m,3H)；ES-LCMS m/z 237(M+2).
Step 3：The bromo- 4- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine
At room temperature, the mixing to the chloro- 4- ethoxy pyridines (75g, 317.1mmol) of the bromo- 2- of 5- in toluene (500mL) (4- methoxyphenyls) methanol (52.6g, 380.6mmol), KOH (35.6g, 634.3mmol) and 18- crown-s 6 are added in thing (8.4g,31.2mmol).At 120 DEG C, the reactant mixture is stirred 2 hours.By mixture distribution in 2- methoxyl group -2- first Between base propane (500mL) and salt solution (800mL).Concentration of organic layers.Pass through post (PE/EA=10:1,Rf=0.5) purify remnants Thing, obtains the bromo- 4- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (72.2g, 221mmol, yield 70%)：1H NMR(400MHz,CD3OD) δ 8.05 (s, 1H), 7.33 (d, J=8.8Hz, 2H), 6.90-6.84 (m, 2H), 6.38 (s, 1H), 5.20 (s, 2H), 4.16-4.05 (m, 2H), 3.77 (s, 3H), 1.43 (q, J=6.8Hz, 3H)；ES-LCMS m/z 338(M+ 2H)。
Step 4：6- methyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters
Stir urea (50g, 833mmol), ethyl 3-oxobutanoate (119g, 916mmol) acton (136g, Solution in 916mmol) 28 hours, while at 80 DEG C, in N2EtOH is distilled out under atmosphere.Then, the mixture is cooled down To 20 DEG C, and add EtOH (800mL), the NaOEt added into said mixture in EtOH (500mL) (85g, 1249mmol), and at 80 DEG C stir the mixture 2 hours, the mixture is cooled to 20 DEG C, be subsequently added into water (1L), AcOH (60mL) is added at 20 DEG C -30 DEG C, the mixture is then filtered, solid is washed with water (200mL), dries, obtains 6- first Base -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (70g, 384mmol, yield 46.2%)：1H NMR(400MHz,DMSO- d6) δ 8.81 (s, 1H), 4.31 (q, J=7.2Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.1Hz, 3H)；LCMS m/z 183.1(M+H)。
Step 5：The chloro- 4- methylpyrimidines -5- carboxylic acid, ethyl esters of 2-
To at 20 DEG C, in N2Lower stirring 6- methyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (62g, POCl is slowly added in solution 340mmol)3(496g,3233mmol).At 80 DEG C, stirring reaction mixture 12 hours. Then, the solution is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution.The organic extract of merging is washed with salt Wash, through Na2SO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified.TLC (PE/ will be passed through EA=10:1,Rf=0.7) find that all fractions comprising product all merge, and concentrate, obtain the chloro- 4- first of 2- of yellow solid Yl pyrimidines -5- carboxylic acid, ethyl esters (9g, 44.9mmol, yield 13.18%)：1H NMR(400MHz,CDCl3)δ9.01(s,1H), 4.41 (q, J=7.1Hz, 2H), 2.82 (s, 3H), 1.41 (t, J=7.1Hz, 3H)；ES-LCMS m/z 201.1(M+H).
Step 6：4- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxas Boron heterocycle pentane -2- bases) pyridine
To at -70 DEG C, in N2Lower stirring the bromo- 4- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (5g, 14.78mmol) in the solution in THF (25mL), during 1 minute, n-BuLi (6.51mL, 16.26mmol) is added portionwise. At -70 DEG C, the reactant mixture is stirred 1 hour.Then, at -70 DEG C, the 2- added into solution in THF (1mL) is different Propoxyl group -4,4,5,5- tetramethyls -1,3,2- dioxaborolans alkane (3.03g, 16.26mmol) is stirred simultaneously.- 70 At DEG C, the solution is stirred 1 hour.The NH of saturation is added into the mixture4Cl solution.Then, the solution is concentrated, and is distributed Between EA and water.By the organic extract of merging salt water washing, through Na2SO4It is dried, filtered and concentrated.Obtain 4- ethoxies Base -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (4g, 10.38mmol, yield 70.2%).TLC (PE/EA=10:1,Rf=0.2):1H NMR(400MHz,CDCl3)δ8.29 (s, 1H), 7.37 (d, J=8.6Hz, 2H), 6.89 (d, J=8.6Hz, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 4.00- 3.97 (m, 2H), 3.80 (s, 3H), 1.40 (t, J=6.9Hz, 3H), 1.33 (s, 12H)；ES-LCMS m/z 386.1(M+H).
Step 7：2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Ethyl ester
To at 20 DEG C, in N24- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- of lower stirring Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (4.99g, 12.96mmol), the chloro- 4- methylpyrimidines -5- carboxylic acids of 2- Ethyl ester (2g, 9.97mmol) and Cs2CO3(6.50g, 19.94mmol) is molten in 1,4- dioxanes (15mL) and water (5.00mL) It is disposable in liquid to add PdCl2(dppf)(0.365g,0.498mmol).In 110 DEG C, heating response container 2 hours.Then, will Solution is concentrated, and is distributed between EA and water.By the organic extract of merging salt water washing, through MgSO4Dry, filter and dense Contracting.Pass through silica gel column chromatography (20%EA:80%PE, 60g silicagel column) purifying residue.TLC (PE/EA=2 will be passed through：1,Rf =0.5) find that all fractions comprising product merge, and concentrate, obtain 2- (4- ethyoxyls -6- ((the 4- first of light yellow solid Oxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acid, ethyl esters (3.5g, 8.27mmol, yield 83%)：1H NMR (400MHz,CDCl3) δ 9.20 (s, 1H), 8.59 (s, 1H), 7.40 (d, J=8.4Hz, 2H), 6.90 (d, J=8.4Hz, 2H), 6.32(s,1H),5.36(s,2H),4.45-4.39(m,2H),4.13-4.05(m,2H),3.81(s,3H),2.87(s,3H), 1.44-1.36(m,6H)；ES-LCMS m/z 424.0(M+H).
Step 8：2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids
To at 20 DEG C, in N2The 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - 4- methylpyrimidine -5- carboxylic acid, ethyl esters (3.5g, 8.27mmol) are disposably added in H in the solution in THF (10mL)2O LiOH in (6.61mL 16.53mmol).Reactant mixture is heated to 50 DEG C 12 hours.Then, the solution is concentrated, is used in combination Dense HCl is neutralized to pH=7.0, stirs simultaneously.Then, the solution is concentrated in a vacuum, obtains 2- (4- ethyoxyls -6- ((4- first Oxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids：1H NMR(400MHz,CD3OD)δ8.86(s,1H), 8.27 (s, 1H), 7.38 (d, J=8.6Hz, 2H), 6.91 (d, J=8.6Hz, 2H), 5.31 (s, 2H), 4.15-4.08 (m, 2H), 3.79 (s, 3H), 2.75 (s, 3H), 1.33 (t, J=6.9Hz, 3H)；LCMS m/z:396.1(M+H).
Intermediate 7：3- (4- amino -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls
Step 1：2,2- dimethyl -3- (2- (trifluoromethyl) phenyl) ethyl propionate
N- is added dropwise to being cooled in mixture of 0 DEG C of the diisopropylamine (8.00mL, 57.1mmol) in THF (300mL) BuLi(24.60mL,61.5mmol).At 0 DEG C, the mixture is stirred 1 hour.Then, to the mixture for being cooled to -30 DEG C The middle solution for adding ethyl isobutyrate (6.12g, 52.7mmol) in THF (2mL).At -30 DEG C, the mixture 1 is stirred small When.At -30 DEG C, 1- (bromoethyl) -2- (trifluoromethyl) benzene (10.5g, 43.9mmol) is added into the mixture in THF Solution in (5mL).At -30 DEG C, the whole mixture is stirred 3 hours, then stirred 12 hours at 25 DEG C.Use NH4Cl (aq) mixture is quenched, and is extracted with EA.By organic layer salt water washing, through MgSO4It is dried, filtered and concentrated.In silica gel Column chromatography (PE/EA=200:1) residue is purified on.TLC (PE/EA=10 will be passed through:1,Rf=0.6) find comprising product All fractions merge, and concentrate, and obtain 2,2- dimethyl -3- (2- (trifluoromethyl) phenyl) ethyl propionate of light yellow solid (10g, 35.3mmol, yield 80.0%)：1H NMR(400MHz,CDCl3)δ:7.62 (d, J=8.0Hz, 1H), 7.41 (t, J= 7.6Hz, 1H), 7.29 (t, J=7.6Hz, 1H), 7.22 (d, J=8.0Hz, 1H), 4.17 (q, J=7.2Hz, 2H), 3.14 (s, 3H), 1.25 (t, J=7.2Hz, 3H), 1.18 (s, 6H)；ES-LCMS m/z 275(M+H).
Step 2：2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) ethyl propionate
To 2,2- dimethyl -3- (2- (trifluoromethyl) phenyl) ethyl propionate (10g, 36.5mmol) being cooled at 0 DEG C In H2SO4Nitro peracid potassium (potassium nitroperoxous acid) is added portionwise in solution in (5mL, 94mmol) (4.05g, 40.1mmol).At 0 DEG C, the mixture is stirred 30 minutes.The mixture is poured into ice-water, and extracted with DCM Take.By organic layer salt water washing, through Na2SO4It is dried and concentrated, obtains 2, the 2- dimethyl -3- (4- nitros -2- of yellow solid (trifluoromethyl) phenyl) ethyl propionate (8.5g, 24.54mmol, yield 67.3%)：1H NMR(400MHz,CDCl3)δ:8.59 (d, J=2.4Hz, 1H), 8.47 (dd, J=2.4,8.8Hz, 1H), 7.82 (d, J=8.4Hz, 1H), 5.97-5.83 (m, 2H)； ES-LCMS m/z 320(M+H)。
Step 3：3- (4- amino -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls
Use H-cube (settings：50 DEG C, 50psi, 24h) hydrogenation 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) Phenyl) the reaction mixing of ethyl propionate (8.5g, 26.6mmol) and Pd/C (0.283g, 2.66mmol) in MeOH (50mL) Thing.Mixture is filtered, and concentrates filtrate.In silica gel column chromatography (PE/EA=10:1) residue is purified on.TLC (PE/ will be passed through EA=5:1, Rf=0.4) find that all fractions comprising product merge and concentrated, obtain the 3- (4- amino -2- of white-yellowish solid (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (7g, 22.42mmol, yield 84.0%)：1H NMR(400MHz, CDCl3)δ:6.98 (d, J=8.4Hz, 1H), 6.91 (d, J=2.4Hz, 1H), 6.71 (dd, J=2.4,8.4Hz, 1H), 4.15 (q, J=6.8Hz, 2H), 3.00 (s, 2H), 1.25 (t, J=7.2Hz, 3H), 1.14 (s, 6H)；ES-LCMS m/z 290(M+ H)。
Intermediate 8：2- (benzyloxy) -4- ethyoxyl -5- iodine pyridines
Step 1：4- ethoxy pyridine 1- oxides
NaOEt is added into mixture of the 4- nitropyridine 1- oxides (50g, 357mmol) in THF (500mL) (48.6g,714mmol).Under 25, the mixture is stirred 16 hours.Concentrate reaction residue.Pass through silica gel column chromatography (DCM/ MeOH=25:1) residue is purified.TLC (DCM/MeOH=25 will be passed through:1,Rf=0.6) find to include all fractions of product Merge, and concentrate, obtain the 4- ethoxy pyridine 1- oxides (25g, 162mmol, yield 45.3%) of dark red solid：1H NMR(400MHz,CD3OD) δ 8.20-8.18 (m, 2H), 7.11-7.10 (m, 2H), 4.21-4.15 (m, 2H), 1.42 (t, J= 7.2Hz,3H)；ES-LCMS m/z 140.0(M+H).
Step 2：4- ethoxy pyridine -2- alcohol
By 4- ethoxy pyridine 1- oxides (5g, 35.9mmol) in Ac2Mixture in O (36.7g, 359mmol) adds Heat backflow 4 hours.Then, solvent is removed under vacuo, and residue is dissolved in MeOH (25mL) and H2In O (25mL), and 25 Stirred 16 hours at DEG C.Concentrate the mixture.Pass through silica gel column chromatography (DCM/MeOH=10:1) residue is purified on.It will pass through TLC (DCM/MeOH=10:1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain dark yellow solid 4- ethoxy pyridine -2- alcohol (2.5g, 16.17mmol, yield 45.0%)：1H NMR(400MHz,CD3OD) δ 7.28 (d, J= 7.6Hz, 1H), 6.07 (d, J=3.2,7.2Hz, 1H), 5.86-7.85 (d, J=2.4Hz, 1H), 4.06-4.01 (m, 2H), 1.38 (t, J=7.2Hz, 3H)；ES-LCMS m/z 140.0(M+H).
Step 3：4- ethyoxyl -5- iodine pyridine -2- alcohol
NIS is added into mixture of the 4- ethoxy pyridine -2- alcohol (2.5g, 17.97mmol) in DMF (30mL) (4.04g,17.97mmol).At 80 DEG C, the mixture is stirred 16 hours.The mixture is concentrated, and by preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying, obtain yellow solid 4- ethyoxyl -5- iodine pyridine -2- alcohol (1.2g, 4.30mmol, yield 23.9%)：1H NMR(400MHz,CD3OD)δ7.70(s,1H),5.92(s,1H),4.15-4.10(m, 2H), 1.48 (t, J=6.8Hz, 3H)；ES-LCMS m/z 265.8(M+H).
Step 4：2- (benzyloxy) -4- ethyoxyl -5- iodine pyridines
Added into mixture of the 4- ethyoxyl -5- iodine pyridine -2- alcohol (800mg, 3.02mmol) in THF (10mL) (bromomethyl) benzene (619mg, 3.62mmol) and silver carbonate (1665mg, 6.04mmol).At 70 DEG C, the mixture 16 is stirred small When.Reaction residue is filtered, and concentrates filtrate.By mixture H2O dilutes, and is extracted with DCM.Merged with salt water washing Organic extract, through MgSO4It is dried, filtered and concentrated.Obtain 2- (benzyloxy) -4- ethyoxyl -5- iodine pyridines (800mg, 1.915mmol, yield 63.4%)：1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.45-7.43(m,2H),7.38- 7.36 (m, 3H), 6.22 (s, 1H), 5.33 (s, 2H), 4.12-4.07 (m, 2H), 1.48 (t, J=6.8Hz, 3H)；ES-LCMS m/z 355.9(M+H)。
Intermediate 9：5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine
Step 1：The fluoro- 4,4- dimethyl -3- oxopentanenitriles of 5,5,5- tri-
N-BuLi is added to being cooled in mixtures of -78 DEG C of the MeCN (3.32mL, 97mmol) in THF (300mL) (56.4mL,141mmol).At -30 DEG C, the mixture is stirred 30 minutes.Then, 3,3,3- tri- are added dropwise into the mixture Fluoro- 2,2- dimethylated methyl propionates (15g, 88mmol).At 25 DEG C, the mixture is stirred 10 hours.Use NH4The Cl aqueous solution is quenched Go out the mixture, and with DCM/MeOH (10:1) extract.Through Na2SO4Organic layer is dried, filters and concentrates.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find to include all grades of divisions of product And, and concentrate, obtain the 5 of light yellow solid, 5,5- tri- fluoro- 4,4- dimethyl -3- oxopentanenitriles (5g, 27.9mmol, yield 31.7%)：1H NMR(400MHz,CDCl3)δ:3.75(s,2H),1.41(s,6H)。
Step 2：5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine
To being cooled to 0 DEG C of hydroxylamine hydrochloride (3.10g, 44.7mmol) in H2NaHCO is added in mixture in O (25mL)3 (3.94g, 46.9mmol) is to adjust pH=7.5.Then, 5,5,5- tri- fluoro- 4,4- dimethyl -3- oxygen are added into the mixture For solution of the valeronitrile (4g, 22.33mmol) in MeOH (25mL).At 65 DEG C, the mixture is stirred 15 hours.In cooling Afterwards, the mixture is acidified to pH=1.0 with dense HCl, be then refluxed for 2 hours.After cooling, the mixing is neutralized with 4M NaOH Thing is to pH=8.0.With DCM/MeOH (10:1) mixture is extracted.Through Na2SO4Organic layer is dried, filters and concentrates, obtain white 5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine (2g, 9.06mmol, yield 40.6%) of color solid：1H NMR(400MHz,CDCl3)δ5.78(s,1H),3.93(s.,2H),1.51(s,6H)；ES-LCMS m/z 195(M+1).
Intermediate 10：3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline
Step 1：4- methyl isophthalic acids-(3- nitros -5- (trifluoromethyl) phenyl) -1H- imidazoles
Suspension of the 4- methyl isophthalic acid H- imidazoles (1.178g, 14.35mmol) in DMF (15mL) is added to the fluoro- 3- of 1- In solution of the nitro -5- (trifluoromethyl) (2g, 9.56mmol) in DMF (15mL).Add Cs2CO3(6.23g, 19.13mmol), and at 80 DEG C, the mixture is stirred 8 hours.The mixture is cooled to room temperature, then concentrate solution, and Distribution is in EA and the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, through MgSO4Dry, filtering is simultaneously Concentration.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC (PE/EA=1 will be passed through：1,Rf=0.5) find bag All fractions containing product merge, and concentrate, and obtain 4- methyl isophthalic acids-(3- nitros -5- (trifluoromethyl) benzene of light yellow solid Base) -1H- imidazoles (800mg, 2.95mmol, yield 30.8%)：1H NMR(400MHz,CD3OD)δ8.61-8.78(m,1H), 8.44-8.51(m,1H),8.31-8.39(m,2H),7.55(s,1H),2.27(s,3H)；ES-LCMS m/z 272.0(M+H).
Step 2：3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline
By 4- methyl isophthalic acids-(3- nitros -5- (trifluoromethyl) phenyl) -1H- imidazoles (800mg, 2.95mmol) in MeOH Suspension in (15mL) is added in suspension of the Pd/C (5.02 μ L, 0.078mmol) in MeOH (15mL).In H2Atmosphere Under, the mixture is placed at 25 DEG C 5 hours.Then, solution is concentrated, and distributed in EA and the NaHCO of saturation3Solution it Between.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing HPLC (MeCN/H2O makees For eluent, alkalescence condition) purifying residue, obtain 3- (4- methyl-1 H-imidazole-1-groups) -5- (fluoroforms of white solid Base) aniline (321.83mg, 1.334mmol, yield 86.0%).TLC (PE/EA=1：1,Rf=0.3):1H NMR(400MHz, CD3OD)δ7.98(s,1H),7.24(s,1H),7.02–6.76(m,3H),2.31-2.17(m,3H)；ES-LCMS m/z 242.1(M+H)。
Intermediate 11：4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) aniline
Step 1：2- methyl -2- (2- (trifluoromethyl) benzyl) diethyl malonate
To being cooled in solution of 0 DEG C of the 2- methyl-malonic esters (4.37g, 25.1mmol) in THF (100mL) Add NaH (1.506g, 37.7mmol).At 0 DEG C, the mixture is stirred 0.5 hour.1- (bromine first is added into the mixture Base) -2- (trifluoromethyl) benzene (5g, 20.92mmol), and at 25 DEG C, stir the mixture 10 hours.TLC (PE/EA=10: 1,Rf=0.6) display initial substance disappearance.Use H2The mixture is quenched in O (50mL), and is extracted with EA (100mL × 2).Will be organic Layer is washed with salt solution (100mL), through Na2SO4It is dried and concentrated.Pass through silica gel column chromatography (PE/EA=50:1) residue is purified. TLC (PE/EA=10 will be passed through:1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain 2- methyl -2- (2- (trifluoromethyl) benzyl) diethyl malonate (4g, 8.02mmol, yield 38.3%)：1H NMR(400MHz,CDCl3) δ= 7.62 (d, J=7.6Hz, 1H), 7.41 (t, J=7.6Hz, 1H), 7.34-7.27 (m, 1H), 7.27-7.21 (m, 1H), 4.26- 4.14(m,4H),3.53(s,2H),1.30-1.21(m,9H)；ES-LCMS m/z:333.2(M+H).
Step 2：2- methyl -2- (4- nitros -2- (trifluoromethyl) benzyl) diethyl malonate
Exist to 2- methyl -2- (2- (trifluoromethyl) benzyl) diethyl malonate (4g, 12.04mmol) for being cooled to 0 DEG C H2SO4Nitro peracid potassium (potassium nitroperoxous acid) is added portionwise in solution in (15mL, 281mmol) (1.339g, 13.24mmol).At 0 DEG C, the mixture is stirred 5 minutes.The mixture is poured into ice-water (100mL), Extracted with EA (100mL × 2).By the Na of organic layer saturation2CO3(100mL × 2) are washed, through Na2SO4It is dried and concentrated, obtains To 2- methyl -2- (4- nitros -2- (trifluoromethyl) benzyl) diethyl malonate (4.5g, the 10.00mmol, production of yellow solid Rate 83%)：1H NMR(400MHz,CDCl3) δ=8.50 (s, 1H), 8.27 (s, 1H), 7.57 (s, 1H), 4.19 (s, 4H), 3.58 (s, 2H), 1.31 (s, 3H), 1.22 (d, J=3.2Hz, 6H)；ES-LCMS m/z:378.1(M+H).
Step 3：2- (4- amino -2- (trifluoromethyl) benzyl) -2- methyl-malonic esters
At 25 DEG C, in H2Under atmosphere, 2- methyl -2- (4- nitros -2- (trifluoromethyl) benzyl) malonate is stirred The reactant mixture of (4.5g, 11.93mmol) and Pd/C (0.127g, 1.193mmol) in MeOH (200mL) 5 hours.Filtering The mixture, and filtrate is concentrated, obtain 2- (4- amino -2- (trifluoromethyl) benzyl) -2- methylmalonic acids of brown oil Diethylester (4.1g, 9.67mmol, yield 81%)：1H NMR(400MHz,CD3OD) δ=7.03-6.93 (m, 2H), 6.79 (d, J =8.4Hz, 1H), 4.21 (q, J=6.8Hz, 4H), 3.36 (s, 2H), 1.26 (t, J=7.2Hz, 6H), 1.20 (s, 3H)；ES- LCMS m/z:348.1(M+H)。
Step 4：2- (4- (double (4- methoxy-benzyls) amino) -2- (trifluoromethyl) benzyl) -2- methylmalonic acid diethyls Ester
At 110 DEG C, stirring 2- (4- amino -2- (trifluoromethyl) benzyl) -2- methyl-malonic esters (4.1g, 11.80mmol), 1- (chloromethyl) -4- methoxybenzenes (5.55g, 35.4mmol) and Cs2CO3(26.9g, 83mmol) is in DMF Mixture in (50mL) 12 hours.Concentrate the mixture.Residue is added in DCM (150mL) and filtered.Filtrate is used Salt solution (100mL) is washed, through Na2SO4It is dried and concentrated, obtains 2- (4- (double (4- methoxy-benzyls) ammonia of yellow oil Base) -2- (trifluoromethyl) benzyl) -2- methyl-malonic esters (3g, 3.83mmol, yield 32.4%)：1H NMR (400MHz,CD3OD) δ=7.45-7.30 (m, 4H), 7.25 (d, J=1.6Hz, 1H), 6.36 (s, 1H), 4.12 (q, J= 6.8Hz, 2H), 3.82 (s, 2H), 1.52 (s, 6H), 1.46 (t, J=6.8Hz, 3H)；ES-LCMS m/z:588.1(M+H).
Step 5：2- (4- ((4- methoxy-benzyls) amino) -2- (trifluoromethyl) benzyl) -2- methylpropane -1,3- glycol
To 2- (4- (double (4- methoxy-benzyls) amino) -2- (trifluoromethyl) benzyl) -2- methyl-props two for being cooled to 0 DEG C LAH (1.111g, 29.3mmol) is added portionwise in the mixture in THF (100mL) in diethyl phthalate (4.3g, 7.32mmol). At 25 DEG C, the mixture is stirred 10 hours.The mixture is quenched with 15%NaOH (aq, 40mL).Through Na2SO4Dry the mixing Thing.After filtration, filtrate is concentrated.In silica gel column chromatography (PE/EA=5:1) residue is purified on.TLC (PE/EA=will be passed through 2：1,Rf=0.35) find that all fractions comprising product merge, and concentrate, obtain 2- (4- ((the 4- methoxies of yellow oil Base benzyl) amino) -2- (trifluoromethyl) benzyl) -2- methylpropane -1,3- glycol (3g, 6.45mmol, yield 88%)：1H NMR(400MHz,CD3OD) δ=7.27 (d, J=8.4Hz, 2H), 7.20 (d, J=8.4Hz, 1H), 6.89-6.83 (m, 3H), 6.73 (dd, J=2.4,8.4Hz, 1H), 4.23 (s, 2H), 3.80-3.72 (m, 4H), 3.34 (s, 1H), 2.67 (s, 2H), 0.63(s,3H)；ES-LCMS m/z:406.1(M+Na).
Step 6：N- (4- methoxy-benzyls) -4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) benzene Amine
To be cooled to 0 DEG C 2- (4- ((4- methoxy-benzyls) amino) -2- (trifluoromethyl) benzyl) -2- methylpropanes - N-BuLi (4.69mL, 11.74mmol) is added in mixture of 1, the 3- glycol (3g, 7.82mmol) in THF (50mL), and is stirred Mix 0.5 hour.Then, 4- methylbenzene -1- sulfonic acid chlorides (2.238g, 11.74mmol) are added into the mixture, and at 25 DEG C Stirring 1 hour.Then, other n-BuLi (4.69mL, 11.74mmol) is added into the mixture, and 2 are stirred at 60 DEG C Hour, then stirred 10 hours at 25 DEG C.Use NH4The mixture is quenched in Cl (aq., 50mL), and is extracted with EA (100mL × 2) Take.Organic layer is concentrated.In silica gel column chromatographies (PE/EA=5:1) residue is purified on.TLC (PE/EA=2 will be passed through：1,Rf =0.5) find that all fractions comprising product merge, and concentrate, obtain N- (4- methoxy-benzyls) -4- of white-yellowish solid ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) aniline (1g, 1.888mmol, yield 24.13%)：1H NMR(400MHz,CDCl3) δ=7.30-7.22 (m, 2H), 6.94-6.80 (m, 4H), 6.68 (d, J=8.4Hz, 1H), 4.65 (d, J=5.6Hz, 2H), 4.29 (d, J=5.2Hz, 2H), 4.24 (s, 2H), 3.85-3.76 (m, 3H), 2.92 (s, 2H), 1.33(s,3H)；ES-LCMS m/z 388.0(M+Na).
Step 7：4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) aniline
In N2Under, to N- (4- methoxy-benzyls) -4- ((3- methy oxetane -3- bases) methyl) -3- (fluoroforms Base) Pd/C (0.291g, 2.74mmol) is added in mixture of the aniline (1g, 2.74mmol) in MeOH (50mL).In H2Gas Under atmosphere (50psi, 50 DEG C, 2h), the mixture is stirred.The mixture is filtered, and concentrates filtrate, the 4- of yield light yellow oil ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) aniline (500mg, 1.788mmol, yield 65.3%)：1H NMR(400MHz,CDCl3)δ:6.97 (s, 1H), 6.90 (d, J=8.4Hz, 1H), 6.79 (d, J=7.6Hz, 1H), 4.65 (d, J=5.2Hz, 2H), 4.29 (d, J=5.2Hz, 2H), 2.93 (s, 2H), 1.59 (s, 2H), 1.32 (s, 3H)；ES-LCMS m/z 246.1(M+H)。
Intermediate 12：1- (5- amino -3- (trifluoromethyl) pyridine -2- bases) ethyl ketone
Step 1：5- nitros -3- (trifluoromethyl) pyridine -2- alcohol
At 0 DEG C, nitric acid is added into the mixture of 3- (trifluoromethyl) pyridine -2- alcohol (2g, 12.26mmol) (1.644mL, 36.8mmol) and H2SO4(12.03g,123mmol).Then, at 25 DEG C, the mixture is stirred 16 hours.So Afterwards, the mixture is warming up to 60 DEG C 5 hours, cool down, and add 150g ice.The mixture is extracted with EA (2 × 100mL), And use H2O (100mL) is washed, and obtains organic layer.By the organic extract of merging salt water washing, through Na2SO4Dry, be concentrated to give To 5- nitros -3- (trifluoromethyl) pyridine -2- alcohol (2.2g, 8.99mmol, yield 73.3%) of brown solid：1H NMR (400MHz,CD3OD) δ 8.91 (d, J=2.43Hz, 1H), 9.42 (d, J=2.43Hz, 1H)；ES-LCMS m/z 209.0(M+ H)。
Step 2：Chloro- 5- nitros -3- (trifluoromethyl) pyridines of 2-
SOCl is added into the mixture of 5- nitros -3- (trifluoromethyl) pyridine -2- alcohol (2g, 9.61mmol)2 (21.04mL, 288mmol) and DMF (0.074mL, 0.961mmol).Then, the mixture is stirred at 80 DEG C 16 hours.It is dense Contract the mixture, is extracted with EA (2 × 100mL), and use H2O (100mL) is washed, and obtains organic layer.By the organic extraction of merging Thing salt water washing, through Na2SO4Dry, concentration, obtain brown solid chloro- 5- nitros -3- (trifluoromethyl) pyridines of 2- (2g, 5.30mmol, yield 55.1%)：1H NMR(400MHz,CD3OD) δ 8.91 (d, J=2.43Hz, 1H), 9.42 (d, J= 2.43Hz,1H)。
Step 3：6- chloro- 5- (trifluoromethyl) pyridine -3- amine
Into mixture of chloro- 5- nitros -3- (trifluoromethyl) pyridines (2g, 8.83mmol) of 2- in AcOH (10mL) one Secondary property adds iron (2.465g, 44.1mmol).At 80 DEG C, the mixture is stirred 15 minutes.The mixture is filtered and concentrated, Then washed and extracted with EA with the NaOH aqueous solution.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC will be passed through (PE/EA=8:1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain the chloro- 5- of 6- of yellow solid (trifluoromethyl) pyridine -3- amine (1g, 4.58mmol, yield 51.9%)：1H NMR(400MHz,CD3OD)δ8.06(s,1H), 7.86 (d, J=8.60Hz, 1H), 7.53 (d, J=8.60Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J=6.62Hz, 3H)；ES-LCMS m/z197.0(M+H).
Step 4：1- (5- amino -3- (trifluoromethyl) pyridine -2- bases) ethyl ketone
Into mixture of 6- chloro- 5- (trifluoromethyl) pyridine -3- amine (200mg, 1.018mmol) in MeOH (3mL) Add 6- chloro- 5- (trifluoromethyl) pyridine -3- amine (200mg, 1.018mmol) NaHCO3(171mg, 2.035mmol) and PdCl2 (dppf)(74.5mg,0.102mmol).Under microwave, at 110 DEG C, in N2The mixture is stirred under atmosphere 30 minutes.So Afterwards, the reaction residue is filtered, and solid is washed by MeOH.Then, 6M HCl are added in the solution, stirred at room temperature Mix 1 hour, then concentrate.By preparing TLC (PE/EA=1：1,Rf=residue 0.6) is purified, obtain the 1- of light yellow solid (5- amino -3- (trifluoromethyl) pyridine -2- bases) ethyl ketone (120mg, 0.500mmol, yield 49.1%)：1H NMR(400MHz, CD3OD) δ 8.10 (d, J=2.43Hz, 1H), 7.30 (d, J=2.43Hz, 1H), 2.56 (s, 3H)；ES-LCMS m/z 205.0 (M+H)。
Intermediate 13：4- ((dimethylamino) methyl) -3- (trifluoromethyl) aniline
Step 1：N, N- dimethyl -4- nitros -2- (trifluoromethyl) benzamide
To at 20 DEG C, in N24- nitros -2- (trifluoromethyl) benzoic acid (10g, 42.5mmol), the dimethylamine of lower stirring Hydrochloride (4.51g, 55.3mmol) and Et3N (17.78mL, 128mmol) is disposably added in the solution in DCM (150mL) HATU(19.41g,51.0mmol).At 20 DEG C, stirring reaction mixture 2 hours.Then, by solution distribution in DCM and saturation NaHCO3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated, obtains N, N- Dimethyl -4- nitros -2- (trifluoromethyl) benzamide (10g, 25.2mmol, yield 59.2%).TLC (PE/EA=5:1,Rf 0.6):1H NMR(400MHz,CDCl3) δ 8.57 (d, J=1.8Hz, 1H), 8.46 (dd, J=2.0,8.4Hz, 1H), 7.58 (d, J=8.4Hz, 1H), 2.79 (s, 6H)；ES-LCMS m/z 263.0(M+H).
Step 2：4- amino-N, N- dimethyl -2- (trifluoromethyl) benzamide
To at 20 DEG C, in N2The N of lower stirring, N- dimethyl -4- nitros -2- (trifluoromethyl) benzamide (10g, It is 25.2mmol) disposable in the solution in MeOH (100mL) to add Pd/C (1g, 9.40mmol).At 20 DEG C, in H2Atmosphere Under, stirring reaction mixture 12 hours.The mixture is filtered, and concentrates filtrate in a vacuum, 4- amino-N, N- diformazan is obtained Base -2- (trifluoromethyl) benzamide (8.3g, 23.59mmol, yield 94.0%).TLC (DCM/MeOH=10:1,Rf= 0.4):1H NMR(400MHz,CDCl3) δ 7.07 (d, J=8.2Hz, 1H), 6.90 (s, 1H), 6.79 (d, J=8.2Hz, 1H), 3.95(br.s.,2H),3.08(s,3H),2.80(s,3H)；ES-LCMS m/z 233.0(M+H).
Step 3：4- ((dimethylamino) methyl) -3- (trifluoromethyl) aniline
To at 20 DEG C, in N24- amino-N, N- dimethyl -2- (trifluoromethyl) benzamide stirred under atmosphere BH is added dropwise in the solution of (8.3g, 23.59mmol) in THF (100mL)3·DMS(11.20mL,118mmol).At 80 DEG C, Stir the reactant mixture 2 hours.MeOH is added into the solution, is then concentrated in a vacuum.Pass through silica gel column chromatography (DCM/ MeOH=30:1) residue is purified.TLC (DCM/MeOH=10 will be passed through:1, Rf=0.4) find to include all fractions of product Merge, and concentrate, obtain light yellow oil 4- ((dimethylamino) methyl) -3- (trifluoromethyl) aniline (4g, 18.33mmol, yield 78.0%)：1H NMR(400MHz,CD3OD) δ 7.99 (d, J=8.0Hz, 1H), 7.73 (s, 1H), 7.67 (d,8.0Hz,1H),4.57(s,2H),2.96(s,6H)；ES-LCMS m/z 219.2(M+H).
Intermediate 14：2- (4- (4- amino-5-fluorines -2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate
Step 1：The bromo- 2- of 4- fluoro- 5- (trifluoromethyl) aniline
NBS is added into mixture of 2- fluoro- 5- (trifluoromethyl) aniline (4g, 22.33mmol) in DMF (60mL) (4.77g, 26.8mmol), it is stirred 2 hours at 20 DEG C.The mixture is concentrated, crude product is obtained, and distribute in acetic acid The NaHCO of ethyl ester (50mL × 3) and saturation3Between (30mL × 3) solution.By the organic extract of merging salt water washing, warp Na2SO4It is dried, filtered and concentrated, does not purify, obtains the bromo- 2- of 4- fluoro- 5- (trifluoromethyl) aniline of brown solid (4.8g, 17.80mmol, yield 80.0%)：1H NMR(400MHz,METHANOL-d4) δ 7.35 (d, J=10.6Hz, 1H), 7.20 (d, J=8.8Hz, 1H)；ES-LCMS m/z 259.0,260.0(M+H).
Step 2：(the bromo- 2- of 4- fluoro- 5- (trifluoromethyl) phenyl) t-butyl carbamate
Added into mixture of the bromo- 2- of 4- fluoro- 5- (trifluoromethyl) aniline (3g, 11.13mmol) in THF (30mL) Boc2O (3.88mL, 16.69mmol) and DMAP (2.039g, 16.69mmol).At 20 DEG C, the mixture is stirred 12 hours. The mixture is concentrated, crude product is obtained, passes through post (PE/EtOAc=10:1,Rf=0.5) purify, obtain in colorless oil (the bromo- 2- of 4- fluoro- 5- (trifluoromethyl) phenyl) t-butyl carbamate (3.1g, 7.53mmol, yield 67.7%)：1H NMR (400MHz,METHANOL-d4) δ 7.82 (dd, J=8.60,4.63Hz, 2H), 1.42 (s, 9H).
Step 3：4- ((tert-butoxycarbonyl) amino) -5- fluoro- 2- (trifluoromethyl) methyl benzoate
In N2Under atmosphere, to (the bromo- 2- of 4- fluoro- 5- (trifluoromethyl) phenyl) t-butyl carbamate (4g, 9.72mmol) PdCl is added in mixture in MeOH (15mL)2(dppf) (0.711g, 0.972mmol) and Et3N(2.71mL, 19.43mmol).At 60 DEG C, under 50psi CO atmosphere, the mixture is stirred 12 hours.TLC (PE/EtOAc=10:1, Rf=0.3) display reaction completion.The mixture is concentrated, crude product is obtained, passes through post (PE/EtOAc=10:1, Rf=0.3) pure Change, obtain 4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) methyl benzoate in colorless oil (2.8g, 7.71mmol, yield 79.0%)：1H NMR (400MHz, CHLOROFORM-d) δ 7.58 (d, J=11.0Hz, 1H), 6.90(br.s.,1H),3.90(s,3H),1.53(s,9H)。
Step 4：(2- fluoro- 4- (hydroxymethyl) -5- (trifluoromethyl) phenyl) t-butyl carbamate
At -78 DEG C, in N2Under atmosphere, to 4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) benzene first Mixture of the sour methyl esters (2.8g, 7.71mmol) in DCM (50mL) adds DIBAL-H (23.14mL, 23.14mmol).- At 78 DEG C, the mixture is stirred 1 hour.The reaction is quenched with water (20mL).By the mixture distribution DCM (50mL × 3) it Between, washed with salt solution (30mL × 3) solution of saturation.By the organic extract of merging through Na2SO4It is dried, filtered and concentrated, obtains To in colorless oil (2- fluoro- 4- (hydroxymethyl) -5- (trifluoromethyl) phenyl) t-butyl carbamate (2.4g, 6.05mmol, yield 78.0%)：1H NMR(400MHz,METHANOL-d4) δ 8.36-8.16 (m, 1H), 7.49 (d, J= 11.9Hz,1H),4.72(s,2H),1.53(s,9H)。
Step 5：4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) benzyl methanesulfonates
At -78 DEG C, to (2- fluoro- 4- (hydroxymethyl) -5- (trifluoromethyl) phenyl) t-butyl carbamate (2.4g, Triethylamine (1.225g, 12.11mmol) and mesyl chloride 6.05mmol) are added in the mixture in DCM (30mL) (1.040g,9.08mmol).At -78 DEG C, the mixture is stirred 0.5 hour.The mixture is extracted with DCM (40mL × 3), Washed with salt solution (30mL × 3) solution of saturation.By the organic extract of merging through Na2SO4It is dried, filtered and concentrated, is in Brown solid thick 4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) benzyls methanesulfonates (2.5g, 4.84mmol, yield 80.0%)：1H NMR(METHANOL-d4, 400MHz) and δ 8.69 (d, J=7.5Hz, 1H), 7.49 (d, J= 11.9Hz,1H),4.62(s,2H),3.42(s,3H),1.55ppm(s,9H)。
Step 6：(the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- trifluoromethyls) phenyl) amino first Tert-butyl acrylate
To 4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) benzyls methanesulfonates (2.5g, 4.84mmol) mixture in MeCN (50mL) adds K2CO3(2.007g, 14.52mmol) and 2- (piperazine -1- bases) ethanol (0.756g, 5.81mmol), it is stirred 2 hours at 50 DEG C.LCMS display reactions are completed.The mixture is concentrated, obtains thick Product, and distribute in ethyl acetate (50mL × 3) and the NaHCO of saturation3Between (30mL × 3).By the organic extract of merging Salt water washing is used, through Na2SO4It is dried, filtered and concentrated, obtains (the fluoro- 4- of the 2- ((4- (2- hydroxyethyls) of brown grease Piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) t-butyl carbamate (2.4g, 4.56mmol, yield 94.0%)：1H NMR(400MHz,METHANOL-d4) δ 8.30-8.20 (m, 1H), 7.53 (s, 1H), 3.68 (t, J=6.2Hz, 2H), 3.60 (s,2H),2.70-2.44(m,10H),1.53(s,9H)；ES-LCMS m/z422.3(M+H).
Step 7：
2- (4- (4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethyl second Acid esters
To (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) carbamic acid uncle Pyridine (1.802g, 22.78mmol), DMAP are added in mixture of the butyl ester (2.4g, 4.56mmol) in DCM (50mL) (0.557g, 4.56mmol) and acetic anhydride (2.326g, 22.78mmol).At 20 DEG C, the mixture is stirred 12 hours.LCMS Display reaction is completed.The mixture is concentrated, crude product is obtained, and distribute in ethyl acetate (30mL × 3) and the NaHCO of saturation3 Between (20mL × 3) solution.By the organic extract of merging salt water washing, through Na2SO4It is dried, filtered and concentrated, passes through post (DCM: MeOH=20:1, Rf=0.5) purify, obtain brown grease 2- (4- (4- ((t-butoxy carbonyl) amino)- 5- fluoro- 2- (trifluoromethyl) benzyl)-piperazine -1- bases) ethylhexoate (2.4g, 4.14mmol, yield 91.0%)：1H NMR (400MHz,METHANOL-d4) δ 8.31-8.19 (m, 1H), 7.55 (d, J=11.9Hz, 1H), 4.24 (t, J=5.5Hz, 2H),3.62(s,2H),2.78-2.67(m,6H),2.56(br.s.,4H),2.05(s,3H),1.53(s,9H)；ES-LCMS m/z 464.3(M+H)。
Step 8：2- (4- (4- amino-5-fluorines -2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate
To 2- (4- (4- ((t-butoxy carbonyl) amino) -5- fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethyl Hydrogen chloride, methanol are added in mixture of the acetic acid esters (2.4g, 4.30mmol) in dichloromethane (DCM) (20mL), and (solvent is closed Thing) (10.75mL, 4N, 43.0mmol), stirred 1 hour at 20 DEG C.LCMS display reactions are completed.The mixture is concentrated, is obtained In solid crude product 2- (4- (4- amino-5-fluorines -2- (trifluoromethyl)-benzyl) piperazine -1- bases) ethylhexoate of yellow (1.8g, 3.72mmol, yield 86.0%)：1H NMR(400MHz,METHANOL-d4) δ 8.90 (d, J=5.3Hz, 1H), 8.16-8.12(m,1H),4.48-4.44(m,2H),4.43-4.31(m,2H),3.85-3.67(m,4H),3.67-3.57(m, 4H), 3.46 (br.s., 2H), 2.12 (d, J=1.3Hz, 3H)；ES-LCMS m/z 364.2(M+H).
Intermediate 15：2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- Methylpyrimidine -5- carboxylic acids
Step 1：3- (2- (benzyloxy) ethyoxyl) bromo- 2- chloropyridines of -5-
5- is added into ((2- bromine oxethyls) methyl) mixture of benzene (4.54g, 21.11mmol) in DMF (40mL) Bromo- 2- chloropyridines -3- alcohol (4g, 19.19mmol), it is stirred 12 hours at 60 DEG C.The mixture is diluted with water (50mL). The mixture is extracted and concentrated with EtOAc (50mL × 3), crude product is obtained, passes through post (PE/EtOAc=10:1,Rf= 0.5) purify, obtain 3- (2- (benzyloxy) ethyoxyl) bromo- 2- chloropyridines of -5- (6.5g, the 17.36mmol, production in yellow solid Rate 90%)：1H NMR(400MHz,METHANOL-d4)δ8.01(s,1H),7.73(s,1H),7.43-7.15(m,5H),4.61 (s,2H),4.30-4.27(m,2H),3.91-3.82(m,2H)；ES-LCMS m/z342.0,344.0(M+H).
Step 2：3- (2- (benzyloxy) ethyoxyl) the bromo- 2- of -5- ((4- methoxy-benzyls) epoxide) pyridine
To mixing of the bromo- 2- chloropyridines (6g, 17.5mmol) of 3- (2- (benzyloxy) ethyoxyl) -5- in toluene (60mL) Potassium hydroxide (1.965g, 35.0mmol), (4- methoxyphenyls) methanol (2.90g, 21.01mmol) and 18- crown-s are added in thing 6(0.463g,1.751mmol).At 120 DEG C, the mixture is stirred 2 hours.The mixture is filtered, and concentrates filtrate, is obtained Crude product, passes through post (PE/EtOAc=5:1,Rf=0.4) purify, obtain 3- (2- (benzyloxy) ethoxies in yellow solid Base) the bromo- 2- of -5- ((4- methoxy-benzyls) epoxide) pyridine (6.8g, 14.16mmol, yield 81%)：1H NMR(400MHz, CHLOROFORM-d) δ 7.78 (d, J=1.8Hz, 1H), 7.39 (d, J=8.4Hz, 2H), 7.33-7.25 (m, 5H), 7.21 (d, J=1.8Hz, 1H), 6.85 (d, J=8.8Hz, 2H), 5.34 (s, 2H), 4.60 (s, 2H), 4.19-4.14 (m, 2H), 3.84- 3.80(m,2H),3.79(s,3H)；ES-LCMS m/z 324.0,326.0(M-PMB+H).
Step 3：3- (2- (benzyloxy) ethyoxyl) -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls - 1,3,2- dioxaborolan alkane -2- bases) pyridine
In N2Under atmosphere, to 3- (2- (benzyloxy) ethyoxyl) the bromo- 2- of -5- ((4- methoxy-benzyls) epoxide) pyridine (4g, 4,4,4', 4', 5,5,5' 9.00mmol) are added in the mixture in 1,4- dioxanes (60mL), 5'- prestoxs -2,2'- is double (1,3,2- dioxaborolans alkane) (2.286g, 9.00mmol), PdCl2(dppf) (0.329g, 0.450mmol) and acetic acid Potassium (2.65g, 27.0mmol), is stirred 3 hours at 110 DEG C.The mixture is filtered, and concentrates filtrate, crude product is obtained, passes through Post (PE/EtOAc=10:1,Rf=0.4) purify, obtain 3- (2- (benzyloxy) ethyoxyl) -2- ((4- first in yellow solid Oxy-benzyl) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (4.5g, 8.21mmol, yield 91%)：1H NMR(400MHz,CHLOROFORM-d)δ8.13(s,1H),7.46-7.35(m,3H), 7.32-7.25 (m, 5H), 6.84 (d, J=8.8Hz, 2H), 5.41 (s, 2H), 4.62 (s, 2H), 4.20 (t, J=4.9Hz, 2H), 3.83 (t, J=4.9Hz, 2H), 3.77 (s, 3H), 1.32 (s, 12H)；ES-LCMS m/z492.2(M+H).
Step 4：2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5-carboxylic acid's ethyl ester
In N2Under atmosphere, to 3- (2- (benzyloxy) ethyoxyl) -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- Tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (4.2g, 8.55mmol) is in 1,4- dioxanes (60mL) and water The chloro- 4- methylpyrimidines -5- carboxylic acid, ethyl esters (1.715g, 8.55mmol) of 2-, PdCl are added in mixture in (20mL)2(dppf) (0.625g, 0.855mmol) and Cs2CO3(5.57g,17.09mmol).At 120 DEG C, the mixture is stirred 2 hours, filter, And filtrate is concentrated, crude product is obtained, passes through post (PE/EtOAc=3:1,Rf=0.4) purify, obtain the 2- (5- of brown solid (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls)-epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acid, ethyl esters (4.1g, 6.77mmol, yield 79%)：1H NMR(400MHz,CHLOROFORM-d)δ9.09(s,1H),8.86(s,1H), 8.11 (d, J=1.3Hz, 1H), 7.39 (d, J=8.8Hz, 2H), 7.23 (d, J=16.3Hz, 5H), 6.81 (d, J=8.4Hz, 2H), 5.42 (s, 2H), 4.59 (s, 2H), 4.39-4.32 (m, 2H), 4.26 (t, J=4.9Hz, 2H), 3.83 (t, J= 4.6Hz, 2H), 3.73 (s, 3H), 2.79 (s, 3H), 1.36 (t, J=7.1Hz, 3H)；ES-LCMS m/z 530.2(M+H).
Step 5：2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5-carboxylic acid
It is phonetic to 2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl In mixture of the pyridine -5- carboxylic acid, ethyl esters (4g, 7.55mmol) in THF (20mL) and water (20mL) add LiOH (0.543g, 22.66mmol).At 50 DEG C, the mixture is stirred 12 hours, then handled with the HCl (2N) of saturation, until obtaining pH=7. The mixture, and dried filtrate are filtered, 2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxyl groups in yellow solid are obtained Benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (2.6g, 4.44mmol, yield 58.8%)：1H NMR (400MHz,METHANOL-d4) δ 8.89 (s, 1H), 8.77 (d, J=1.8Hz, 1H), 8.20 (d, J=1.8Hz, 1H), 7.42 (d, J=8.8Hz, 2H), 7.35-7.12 (m, 5H), 6.88 (d, J=8.8Hz, 2H), 5.41 (s, 2H), 4.61 (s, 2H), 4.34-4.25(m,2H),3.90-3.82(m,2H),3.77(s,3H),2.77(s,3H):ES-LCMS m/z 502.2(M+H)。
Intermediate 16：3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzsulfamide
Step 1：3- nitros -5- (trifluoromethyl) benzene -1- sulfonic acid chlorides
Through 15 minutes, at -10 DEG C in stirred under N2 atmosphere 3- nitros -5- (trifluoromethyl) aniline (4.6g, 22.32mmol) it is added dropwise in the solution in dense HCl (20mL) and acetic acid (6mL) in H2Natrium nitrosum in O (3mL) (1.694g,24.55mmol).The reactant mixture is stirred 45 minutes, while keeping the temperature between -10 DEG C to -5 DEG C.When When diazotising is completed, glacial acetic acid (60mL) is placed in 100mL beakers, and carry out magnetic agitation.By with immersion acetic acid surface The bubbler tube at following sintering end introduces sulfur dioxide, until obvious saturation.Into the solution add copper chloride (I) (0.552g, 5.58mmol).Continue to introduce sulfur dioxide until yellow-green suspension becomes dark green.During this period (15-20min), big portion The solid dissolving divided.Then, the mixture is placed in ice bath, cooled down, stirred simultaneously.When temperature is close to 10 DEG C, through 10 points Diazo-reaction mixture is added portionwise into the sulfur dioxide solution during clock.There is considerable bubble after each add Foam, and temperature rises during adding, but not over 30 DEG C.After all diazonium salt mixtures are added, by this Mixture is poured into frozen water.Then, by solution distribution in EtOAc (60mL) and the NaHCO of saturation3(30mL) solution it Between.The organic layer of merging is washed with salt solution (20mL), through Na2SO4It is dried, filtered and concentrated, obtains in the thick of yellow oil Product 3- nitros -5- (trifluoromethyl) benzene -1- sulfonic acid chlorides (4.42g, 9.16mmol, yield 41.0%).Pass through TLC (PE/ EtOAc=10:1,Rf=0.5) detect crude product：1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.85(s,1H),8.61 (s,1H)。
Step 2：N- (2- (dimethylamino) ethyl) -3- nitros -5- (trifluoromethyl) benzsulfamide
To 3- nitros -5- (trifluoromethyl) benzene -1- sulfonic acid chlorides (2g, 6.91mmol) stirred at 25 DEG C in DCM It is disposable in solution in (15mL) to add N, N- dimethyl ethane -1,2- diamines (0.913g, 10.36mmol).At 25 DEG C, In N2Under atmosphere, stirring reaction mixture 1 hour.Lcms analysis shows that initial substance disappears, by solution distribution at DCM (60mL) With the NaHCO of saturation3Between (30mL) solution.The organic extract of merging is washed with salt solution (20mL), through Na2SO4Dry, Filter and concentrate.Pass through silica gel column chromatography (DCM/MeOH=20:1 to 10:1) thick material is purified.TLC (DCM/MeOH will be passed through =10:1,Rf=0.4) find that all fractions comprising product merge, and concentrate, obtain the N- (2- (dimethyl of yellow oil Amino) ethyl) -3- nitros -5- (trifluoromethyl) benzsulfamide (1.200g, 3.41mmol, yield 49.4%)：1H NMR (400MHz,CDCl3)δ8.90(s,1H),8.67(s,1H),8.46(s,1H),3.14-3.07(m,2H),2.97(s,1H), 2.45-2.39(m,2H),2.15(s,6H)；ES-LCMS m/z:342.1(M+H).
Step 3：3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzsulfamide
To in N2N- (2- (dimethylamino) ethyl) -3- nitros -5- (trifluoromethyl) benzsulfamide stirred under atmosphere It is disposable in the solution of (1.2g, 3.52mmol) in methanol (20mL) to add Pd/C (10%, 0.374g, 0.352mmol).So Afterwards, under vacuo, the suspension is deaerated, and use H2Purging three times.At 25 DEG C, in 15psi H2Under atmosphere, stir this and mix Compound 12 hours.Lcms analysis shows that initial substance disappears.Reactant mixture is filtered via Celite pad, and with DCM (30mL) Wash filter cake.The filtrate of merging is concentrated into anhydrous, obtains the crude product 3- amino-N- (2- (dimethylaminos of yellow oil Base) ethyl) -5- (trifluoromethyl) benzsulfamide (1g, 3.08mmol, yield 88.0%)：1H NMR(400MHz,CDCl3)δ 7.43 (s, 1H), 7.32 (s, 1H), 7.04 (s, 1H), 4.19 (br.s., 2H), 3.00 (t, J=5.8Hz, 2H), 2.34 (t, J =5.8Hz, 2H), 2.10 (s, 6H)；ES-LCMS m/z:312.1(M+H).
Intermediate 17：(1- (4- amino -2- (trifluoromethyl) phenyl) ethyl) t-butyl carbamate
Step 1：2- (4- amino -2- (trifluoromethyl) phenyl) propionamide
At 60 DEG C, stirring 2- (4- amino -2- (trifluoromethyl) phenyl) propionitrile (800mg, 3.74mmol) is in sulfuric acid Mixture in (8mL, 150mmol) 2 hours.The reactant mixture is slowly added in frozen water (20mL), and passed through 50%NaOH excess solution alkalization.The mixture is extracted with EtOAc (50mL × 2).By the organic extract salt solution of merging Washing, through MgSO4Be dried, filtered and concentrated, obtain 2- (4- amino -2- (trifluoromethyl) phenyl) propionamide (700mg, 2.86mmol, yield 77.0%).TLC (PE/EtOAc=1：1,Rf=0.5)1H NMR(400MHz,CD3OD)δ7.39(d,J =8.0Hz, 1H), 6.99 (d, J=2.0Hz, 1H), 6.89 (dd, J=2.4,8.4Hz, 1H), 3.90 (q, J=7.2Hz, 1H), 1.44 (d, J=7.2Hz, 3H)；ES-LCMS m/z 233.0(M+H).
Step 2：2- (4- (1,3- dioxoisoindolin -2- bases) -2- (trifluoromethyl) phenyl) propionamide
It is mixed in acetic acid (10mL) to 2- (4- amino -2- (trifluoromethyl) phenyl) propionamide (700mg, 3.01mmol) Isobenzofuran -1,3- diketone (670mg, 4.52mmol) is added in compound.At 120 DEG C, the mixture is stirred 16 hours.Will The mixture is concentrated, and adds the NaHCO of saturation3Solution (10mL), and extracted with EtOAc (50mL × 2).By organic extraction of merging Thing salt water washing is taken, through Na2SO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EtOAc=5:1~2：1) purify Crude product.TLC (PE/EtOAc=2 will be passed through：1,Rf=0.5) find that all fractions comprising product merge, and concentrate, obtain White-yellowish solid 2- (4- (1,3- dioxoisoindolin -2- bases) -2- (trifluoromethyl) phenyl) propionamide (900mg, 2.434mmol, yield 81.0%)：1H NMR(400MHz,CD3OD)δ8.03-7.96(m,2H),7.95-7.88(m,3H), 7.86 (d, J=2.0Hz, 1H), 7.78 (dd, J=1.6,8.4Hz, 1H), 4.16 (q, J=6.8Hz, 1H), 1.58 (d, J= 7.2Hz,3H)；ES-LCMS m/z 363.0(M+H).
Step 3：(1- (4- (1,3- dioxoisoindolin -2- bases) -2- (trifluoromethyl) phenyl) ethyl) carbamic acid The tert-butyl ester
To 2- (4- (1,3- dioxoisoindolin -2- bases) -2- (trifluoromethyl)-phenyl)-propionamide (900mg, 2.484mmol) be added portionwise in the mixture in the tert-butyl alcohol (15mL) [double (trifluoroacetyl epoxide) iodine] benzene (1602mg, 3.73mmol).At 85 DEG C, the mixture is stirred 30 minutes.Into said mixture add pyridine (0.603mL, 7.45mmol).At 85 DEG C, the reactant mixture is stirred 2 hours, then concentrate, obtain crude product.Pass through silica gel column chromatography (PE/EtOAc=5:1~2：1) thick material is purified.TLC (PE/EtOAc=2 will be passed through：1,Rf=0.6) find comprising product All fractions merge and concentrated, and obtain (1- (4- (1,3- dioxoisoindolin -2- bases) -2- (fluoroforms of light yellow solid Base) phenyl) ethyl) t-butyl carbamate (660mg, 1.291mmol, yield 52.0%)：1H NMR(400MHz,CD3OD)δ 7.97 (dd, J=3.2,5.6Hz, 2H), 7.88 (dd, J=3.2,5.6Hz, 2H), 7.80-7.78 (m, 2H), 7.76-7.72 (m,1H),5.15-5.08(m,1H),1.40(s,12H)；ES-LCMS m/z457.0(M+Na).
Step 4：(1- (4- amino -2- (trifluoromethyl) phenyl) ethyl) t-butyl carbamate
To (1- (4- (1,3- dioxoisoindolin -2- bases) -2- (trifluoromethyl) phenyl) ethyl) the tertiary fourth of carbamic acid Hydrazine (0.281mL, 7.60mmol) is added in mixture of the ester (660mg, 1.519mmol) in ethanol (10mL).At 80 DEG C, Stir the mixture 3 hours.Then, the mixture is filtered and concentrated.By preparing TLC (PE/EtOAc=1：1,Rf= 0.6) thick material is purified, (1- (4- amino -2- (trifluoromethyl) phenyl)-ethyl) tertiary fourth of carbamic acid of white-yellowish solid is obtained Ester (400mg, 1.052mmol, yield 69.2%)：1H NMR(400MHz,CD3OD) δ 7.31 (d, J=8.4Hz, 1H), 6.93- 6.92(m,1H),6.88-6.86(m,1H),5.00-4.99(m,1H),1.39-1.29(m,12H)ES-LCMS m/z 327.1 (M+Na)。
Intermediate 18：4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) aniline
Step 1：2- (4- nitros -2- (trifluoromethyl) phenyl) acetic acid
To in ice bath in 2- (2- (trifluoromethyl) phenyl) acetonitrile (3g, 16.20mmol) stirred at 0 DEG C in H2SO4 Be slowly added in solution in (15mL) nitro peracid potassium (potassium nitroperoxous acid) (1.638g, 16.20mmol).Then, at 0 DEG C, the mixture is stirred 1 hour.TLC (PE/EA=2：1,Rf=0.35) analysis show Beginning material is disappeared, and adds 15g ice, and the mixture is heated into 110 DEG C 15 hours.TLC (PE/EA=1：1,Rf=0.25) Analysis shows that initial substance disappears, and observes desired product.The reactant mixture is cooled to 20 DEG C, is added dropwise and adds 20mL 20mL frozen water, and stir 30 minutes.Suspension is filtered through Celite pad, filter cake is washed with water (10mL × 3), It is dried in a vacuum, obtains pure products 2- (4- nitros -2- (trifluoromethyl) phenyl) acetic acid (3.5g, 13.35mmol, yield 82.0%)：1H NMR(400MHz,CD3OD) δ 8.52 (d, J=2.0Hz, 1H), 8.47-8.44 (m, 1H), 7.78 (d, J= 8.4Hz,1H),3.98(s,2H)。
Step 2：2- (4- nitros -2- (trifluoromethyl) phenyl) -1- (pyrrolidin-1-yl) ethyl ketone
To 2- (4- nitros -2- (trifluoromethyl) phenyl) solution of the acetic acid (2.5g, 10.03mmol) in pyridine (20mL) In it is disposable add pyrrolidines (1.070g, 15.05mmol), 2,4,6- tripropyls -1,3,5,2,4,6- trioxas are then added dropwise Triphosphane (trioxatriphosphinane) 2,4,6- trioxides (13mL, 10.03mmol).At 20 DEG C, stir this and mix Compound 3 hours.Lcms analysis shows that initial substance disappears.40mL frozen water is added, and this is extracted with EtOAc (50mL × 2) and is mixed Compound.The organic layer thing of merging is washed with salt solution (30mL), is evaporated, obtains crude product, passes through silica gel column chromatography (DCM/MeOH =20:1 to 15:1) purify, obtain pure products 2- (4- nitros -2- (trifluoromethyl) phenyl) -1- (pyrroles of brown solid Alkane -1- bases) ethyl ketone (2.189g, 5.36mmol, yield 53.4%)：1H NMR(400MHz,CD3OD) δ 8.51 (d, J=2.2Hz, 1H), 8.45-8.43 (m, 1H), 7.69 (d, J=8.4Hz, 1H), 4.03 (s, 2H), 3.60 (t, J=6.8Hz, 2H), 3.45 (t, J=7.0Hz, 2H), 2.09-2.00 (m, 2H), 1.96-1.89 (m, 2H)；ES-LCMS:m/z 303.1(M+H).
Step 3：2- (4- amino -2- (trifluoromethyl) phenyl) -1- (pyrrolidin-1-yl) ethyl ketone
To in N22- (4- nitros -2- (trifluoromethyl) phenyl) -1- (pyrrolidin-1-yl) ethyl ketone stirred under atmosphere It is disposable in the solution of (2.19g, 7.25mmol) in methanol (15mL) to add Pd/C (10%, 0.077g, 0.725mmol). Suspension is deaerated under vacuo, and use H2Purging three times.Lcms analysis shows that initial substance disappears, and reactant mixture is filtered Filter cake is washed by Celite pad, and with MeOH.The filtrate of merging is concentrated into anhydrous, obtains crude product, pass through silicagel column color Compose (PE/EA=3:1 to 1：1) purify, obtain pure products 2- (4- amino -2- (trifluoromethyl) phenyl) -1- in yellow solid (pyrrolidin-1-yl) ethyl ketone (1.44g, 4.97mmol, yield 68.6%)：1H NMR(400MHz,CDCl3) δ 7.17 (d, J= 8.4Hz, 1H), 6.94 (d, J=2.4Hz, 1H), 6.80-6.77 (m, 1H), 3.80 (br.s., 2H), 3.69 (s, 2H), 3.51 (t, J=6.8Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 1.99-1.91 (m, 2H), 1.90-1.81 (m, 2H)；ES-LCMS: m/z 273.1(M+H)。
Step 4：4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) aniline
To 2- (4- amino -2- (trifluoromethyl) phenyl) -1- (pyrrolidin-1-yl) ethyl ketone (1.44g, 5.29mmol) four BH is added portionwise in solution in hydrogen furans (THF) (15mL)3.DMS(3.01mL,31.7mmol).Then, at 18 DEG C, stir Mix the mixture 12 hours.After lcms analysis shows that initial substance disappears, the mixture is cooled to 0 DEG C in ice bath. Then, the mixture is quenched in the MeOH for 2mL being added dropwise.Solvent is removed under vacuo.Residue is dissolved in DCM (60mL), is used in combination H2O (20mL) and salt solution (20mL) washing.Through Na2SO4Organic layer is dried, filters and concentrates, obtain the 4- (2- (pyrroles of yellow solid Cough up alkane -1- bases) ethyl) -3- (trifluoromethyl) aniline (1.2g, 4.04mmol, yield 76.0%)：1H NMR(400MHz, CDCl3) δ 7.17 (d, J=8.2Hz, 1H), 6.92 (d, J=2.0Hz, 1H), 6.79 (dd, J=1.8,8.2Hz, 1H), 3.79 (br.s.,2H),3.36-3.24(m,2H),3.23-3.14(m,2H),2.93-2.84(m,2H),2.82-2.71(m,2H), 2.26-2.13 (m, 2H), 1.91 (t, J=7.2Hz, 2H)；ES-LCMS:m/z 271.0(M+BH3),259.1(M+H)。
Intermediate 19：2- chlorine pyrimidine -5- amine
At 0 DEG C, to the chloro- 5- nitro-pyrimidines (5g, 31.3mmol) of 2- and zinc (20.49g, 313mmol) in methanol Ammonium chloride (16.77g, 313mmol) is added in solution in (150mL).At 25 DEG C, obtained mixture is stirred 16 hours. After lcms analysis shows that initial substance disappears, the mixture is filtered.Filtrate is concentrated, crude product is obtained, passes through column chromatography (PE/EA=3/1 to 1/1) is purified.TLC (PE/EA=1/1, R will be passed throughf=0.5) find to include all grades of divisions of product And, and concentrate, obtain the 2- chlorine pyrimidine -5- amine (1g, 7.72mmol, yield 24.63%) of yellow solid：1H NMR(400MHz, METHANOL-d4)δ8.04(s,2H)；ES-LCMS m/z 130.1(M+H).
Intermediate 20：4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) aniline
Step1：1- ethyls -4- (5- fluoro- 2- (trifluoromethyl) benzyl) piperazine
At 20 DEG C, stirring 5- fluoro- 2- (trifluoromethyl) benzaldehyde (2g, 10.41mmol) and 1- ethyl piperazidines The solution of (1.783g, 15.62mmol) in DCM (60mL).After 2 hr, sodium triacetoxy borohydride is added (6.62g,31.2mmol).At 20 DEG C, stir obtained mixture and stay overnight.Show that initial substance disappears it in lcms analysis Afterwards, the mixture is dissolved in H2In O (30mL), and with the NaHCO of saturation3Adjust to pH 8.By organic layer salt water washing, and Through Na2SO4Dry.After filtration, filtrate is concentrated, crude product is obtained, passes through column chromatography (DCM/MeOH=0 to 20:1) purify, Obtain 1- ethyls -4- (5- fluoro- 2- (trifluoromethyl) benzyl) piperazine (3g, 8.74mmol, yield 84%) of yellow oil：1H NMR(400MHz,CD3OD) δ 7.77 (dd, J=8.8,5.2Hz, 1H), 7.63 (dd, J=10.0,2.0Hz, 1H), 7.21 (dt, J=8.4,2.4Hz, 1H), 3.80 (s, 2H), 3.24 (br.s., 4H), 3.13 (q, J=7.6Hz, 2H), 2.77 (br.s., 4H), 1.34 (t, J=7.2Hz, 3H)；ES-LCMS m/z:291.1(M+H).
Step 2：1- ethyls -4- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) piperazine
To 1- ethyls -4- (5- fluoro- 2- (trifluoromethyl) benzyl) piperazines (3g, 10.33mmol) sulfuric acid (6ml, Nitric acid (0.716g, 11.37mmol) is added in solution in 113mmol).At room temperature, the mixture that stirring is obtained is stayed overnight. At 50 DEG C, the mixture is stirred 2 hours.(PE/EA=10 is analyzed in TLC:1) after display initial substance disappears, NaOH is passed through The aqueous solution adjusts the mixture to pH 8, and is extracted with EA (50mL × 2).By organic layer H2O (50mL) and salt solution (50mL) is washed, then through Na2SO4Dry and filter.Filtrate is concentrated, 1- ethyls -4- (the fluoro- 4- nitre of 5- of yellow oil is obtained Base -2- (trifluoromethyl) benzyl)-piperazine (2.2g, 6.56mmol, yield 63.5%)：1H NMR(400MHz,CD3OD)δ8.39 (d, J=7.0Hz, 1H), 7.92 (d, J=12.0Hz, 1H), 3.75 (s, 2H), 2.60-2.47 (m, 10H), 1.14-1.10 (m, 3H)；ES-LCMS m/z 336.1(M+H).
Step 3：4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) aniline
To 1- ethyls -4- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) piperazines (2.2g, 6.56mmol) and zinc Ammonium chloride (3.51g, 65.6mmol) is added portionwise in the solution of (4.29g, 65.6mmol) in methanol (100mL).At 20 DEG C Under, stir obtained mixture 12 hours.After lcms analysis shows that initial substance disappears, the mixture is filtered.Concentration filter Liquid, obtains crude product, by preparing HPLC (mobile phase As: containing 0.05%NH3.H2The O aqueous solution/Mobile phase B MeCN/ streams Speed:80mL/min/ is detected: UV 220nm/254nm/ posts：Phenomenex Gemini C18250*50mm, 10um/ column temperatures： The distribution description of RT/ gradients：40-70 (B%)) purify, 4- ((4- ethyl piperazidine -1- bases) the methyl) -2- for obtaining yellow solid is fluoro- 5- (trifluoromethyl) aniline (0.7g, 2.265mmol, yield 34.5%)：1H NMR(400MHz,CD3OD) δ 7.31 (d, J= 12.6Hz, 1H), 7.10 (d, J=8.6Hz, 1H), 3.51 (s, 2H), 2.74-2.15 (m, 10H), 1.10 (t, J=7.3Hz, 3H)；ES-LCMS m/z:306.1(M+H).
Intermediate 21：
2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidines -5- Carboxylic acid
Step 1：The chloro- 4- of 2- (2- methoxy ethoxies) pyridine
To being cooled in mixture of 0 DEG C of the 2-methyl cellosolve (5.62g, 73.8mmol) in THF (100mL) in batches 60%NaH (2.95g, 73.8mmol) is added, the chloro- 4- nitropyridines (9g, 56.8mmol) of 2- are subsequently added into.At 25 DEG C, stir Mix whole mixture 10 hours.The mixture is concentrated, residue is obtained, passes through silica gel column chromatography (PE/EtOAc=8:1~2：1) Purifying.Pass through TLC (PE/EtOAc=5:1,Rf=0.5) find that all fractions containing product merge, and concentrate, obtain yellow The chloro- 4- of 2- (2- methoxy ethoxies) pyridine (11g, 55.7mmol, yield 98.0%) of grease：1H NMR(400MHz, CDCl3) δ 8.15 (d, J=4.6Hz, 1H), 6.87-6.72 (m, 2H), 4.19-4.08 (m, 2H), 3.77-3.67 (m, 2H), 3.41(s,3H)；LCMS(m/z)188.1(M+H).
Step 2：The chloro- 4- of the bromo- 2- of 5- (2- methoxy ethoxies) pyridine
To the chloro- 4- of 2- (2- methoxy ethoxies) pyridine (11g, 58.6mmol) and H2SO4(100mL, 1876mmol's) is molten NBS (11.48g, 64.5mmol) is added in liquid.Then, at 50 DEG C, the mixture is stirred 4 hours.Be cooled to room temperature it Afterwards, the mixture is poured into cold water (500mL), pH=7.5 is neutralized to 2mol/L NaOH.With EtOAc (200mL × 3) mixture is extracted.Through Na2SO4Organic layer is dried, filters and concentrates.Pass through silica gel column chromatography (5%EtOAc:95% oil Ether, 100g silicagel columns) purification of crude product.TLC (EtOAc will be passed through：Petroleum ether=1：5,Rf=0.6) find to include the institute of product Have fraction merging, and concentrate, obtain yellow oil the bromo- 2- of 5- chloro- 4- (2- methoxy ethoxies) pyridine (6.9g, 23.30mmol, yield 39.7%)：1H NMR(400MHz,CDCl3)δ8.31(s,1H),6.83(s,1H),4.27-4.18(m, 2H),3.83-3.76(m,2H),3.45(s,3H)；ES-LCMS m/z 266.0,268.0(M+H).
Step 3：The bromo- 2- of 5- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridine
To the bromo- 2- of 5- chloro- 4- (2- methoxy ethoxies) pyridine (4.0g, 15.01mmol), 18- crown-s 6 (0.198g, 0.750mmol) and in mixture of (4- methoxyphenyls) methanol (2.488g, 18.01mmol) in toluene (50mL) add KOH(2.53g,45.0mmol).At 110 DEG C, whole mixture is stirred 2 hours.The mixture is filtered and concentrated, obtains thick Product, is purified by silica gel column chromatography (10%EtOAc: 90% petroleum ether, 50g silicagel columns).TLC (EtOAc: oil will be passed through Ether=1：5, Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain bromo- the 2- ((4- of 5- of white solid Methoxy-benzyl) epoxide) -4- (2- methoxy ethoxies) pyridine (5.0g, 12.22mmol, yield 81.0%)：1H NMR (400MHz,CDCl3) δ 8.13 (s, 1H), 7.38 (d, J=8.8Hz, 2H), 6.92 (d, J=8.4Hz, 2H), 6.27 (s, 1H), 5.27 (s, 2H), 4.20-4.12 (m, 2H), 3.82 (s, 3H), 3.80 (d, J=4.4Hz, 2H), 3.48 (s, 3H)；ES-LCMS m/z:368.1,370.1(M+H)。
Step 4：2- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) -5- (4,4,5,5- tetramethyl -1, 3,2- dioxaborolan alkane -2- bases) pyridine
Under nitrogen atmosphere, at -78 DEG C, to the bromo- 2- of 5- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) Pyridine (2g, 5.43mmol) is slowly added BuLi (3.26mL, 2.5N, 8.15mmol) in the mixture in THF (30mL)； At -78 DEG C, the mixture is stirred 0.5 hour.Then, addition 2- isopropoxies -4,4 into the mixture, 5,5- tetramethyls - 1,3,2- dioxaborolan alkane (1.213g, 6.52mmol), and stir at -78 DEG C the reactant mixture 1 hour.So Afterwards, the mixture is concentrated, residue is obtained, is extracted with DCM (30mL × 2).Organic extract is washed with salt solution (30mL), is passed through Na2SO4Be dried, filtered and concentrated, obtain 2- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) of yellow solid - 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (2.5g, 2.71mmol, yield 49.9%) ：1H NMR(400MHz,CD3OD) δ 7.34 (d, J=8.4Hz, 3H), 6.92-6.88 (m, 3H), 5.25-5.22 (m, 2H), 4.14-4.10(m,2H),3.77(s,3H),3.48-3.43(m,2H),3.41-3.38(m,3H),1.35-1.29(m,12H)； LCMS(m/z):416.1(M+H)。
Step 5：2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methyl is phonetic Pyridine -5- carboxylic acid, ethyl esters
At 80 DEG C, in N2Under atmosphere, 2- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) -5- is stirred (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (2g, 4.82mmol), PdCl2(dppf) The chloro- 4- methylpyrimidines -5- carboxylic acid, ethyl esters (1.159g, 5.78mmol) of (0.176g, 0.241mmol), 2-, K2CO3(4.82ml, 9.63mmol) the suspension in 1,4- dioxanes (20ml) and water (5ml) 2 hours.The mixture is concentrated, residue is obtained, Extracted with DCM (40mL × 2).With salt solution (40mL) organic extract, through Na2SO4It is dried, filtered and concentrated, and passes through silicagel column Chromatogram (10%EtOAc：90% petroleum ether, 20g silicagel columns) purifying.TLC (EtOAc will be passed through:Petroleum ether=1：5,Rf=0.5) It was found that all fractions comprising product merge, and concentrate, obtain 2- (6- ((4- methoxy-benzyls) epoxide) -4- of white solid (2- methoxy ethoxies) pyridin-3-yl) -4- methyl-pvrimidine -5- carboxylic acid, ethyl esters (1.1g, 1.941mmol, yield 40.3%) ：1H NMR(400MHz,CD3OD) δ 9.18-9.13 (m, 1H), 8.50-8.44 (m, 1H), 7.39 (d, J=8.4Hz, 2H), 6.95-6.89(m,2H),6.56-6.51(m,1H),5.49(s,1H),5.33(s,1H),4.47-4.36(m,3H),4.25- 4.17(m,2H),3.81-3.77(m,3H),3.76-3.71(m,2H),3.34(s,3H),2.85(s,2H),1.45-1.40(m, 3H)；LCMS(m/z)454.1(M+H).
Step 6：2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methyl is phonetic Pyridine -5- carboxylic acids
At 60 DEG C, stirring 2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) - 4- methylpyrimidine -5- carboxylic acid, ethyl esters (1.1g, 2.426mmol), lithium hydroxide, H2O (0.305g, 7.28mmol) is in THF Suspension in (15mL) and water (5mL) 12 hours.The mixture is concentrated, residue is obtained.By prepare HPLC (post: Phenomenex Gemini C18250*5010u；Mobile phase: 0.05% ammoniacal liquor-ACN；Gradient: from 12 to 42 in 30min B；Flow velocity: 90mL/min；Wavelength: 220/254nm) purification of crude product, and freeze, obtain 2- (6- ((the 4- methoxies of white solid Base benzyl) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (800mg, 1.692mmol, Yield 69.8%)：1H NMR(400MHz,CD3OD) δ 8.93-8.86 (m, 1H), 8.35-8.27 (m, 1H), 7.39 (d, J= 8.8Hz,2H),6.94-6.85(m,2H),6.51(s,1H),5.32(s,2H),4.23-4.18(m,2H),3.81-3.77(m, 3H),3.72-3.68(m,2H),3.31(br.s.,3H),2.78-2.74(m,3H)；LCMS(m/z):426.1(M+H).
Intermediate 22：The fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl) aniline
Step 1：1- (5- fluoro- 2- (trifluoromethyl) benzyl) -4- methyl piperazines
At 25 DEG C, stirring 5- fluoro- 2- (trifluoromethyl) benzaldehyde (4g, 20.82mmol) and 1- methyl piperazines (3.13g, 31.2mmol) the solution in DCM (150mL).After 2 hr, sodium cyanoborohydride (3.93g, 62.5mmol) is added. At 25 DEG C, obtained mixture is stirred 16 hours.Lcms analysis shows that initial substance disappears.Use H2O (80mL) washs the mixing Thing.Organic layer is washed with salt solution (50mL), and through Na2SO4Dry.After filtration, filtrate is concentrated, crude product is obtained, passes through Column chromatography (DCM to DCM/MeOH=20/1) is purified.TLC (DCM/MeOH=20/1, R will be passed throughf=0.4) find to include product All fractions merge, and concentrate, obtain 1- (5- fluoro- 2- (trifluoromethyl) benzyl) -4- methyl piperazines of yellow oil (2.41g, yield 37%)：1H NMR (400MHz, METHANOL-d4) d=7.73 (dd, J=8.4,5.6Hz, 1H), 7.60 (d, J=10.0Hz, 1H), 7.17 (t, J=8.4Hz, 1H), 3.70 (s, 2H), 2.55 (brs, 8H), 2.32 (s, 3H)；ES- LCMS m/z:277.2(M+H)。
Step 2：1- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) -4- methyl piperazines
To 1- (5- fluoro- 2- (trifluoromethyl) benzyl) -4- methyl piperazines (3g, 10.86mmol) in sulfuric acid (20ml) Nitric acid (0.728mL, 16.29mmol) is added dropwise in solution.At 60 DEG C, obtained mixture is stirred 16 hours.Lcms analysis shows Show that initial substance disappears.The mixture is poured into ice-water, and adjusted with the NaOH aqueous solution to pH=8.With EA (50mL × 2) mixture is extracted.Organic layer is washed with salt solution (30mL), it is dried over sodium sulfate, filter and concentrate, obtain brown solid 1- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) -4- methyl piperazines (3.3g, 9.76mmol, yield 90%)：1H NMR (400MHz,METHANOL-d4) δ 8.41 (d, J=7.2Hz, 1H), 7.93 (d, J=12.0Hz, 1H), 3.78 (s, 2H), 2.78 (brs,4H),2.62(br.s.,4H),2.48(s,3H)；ES-LCMS m/z:322.1(M+H).
Step 3：The fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl) aniline
At 25 DEG C, in H2Under atmosphere, 1- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) -4- methyl piperazines are stirred The solution of (3.3g, 10.27mmol) and 10%Pd/C (0.4g, 0.376mmol) in methanol (100mL) 2 hours.Lcms analysis Show that initial substance disappears.Filter the mixture.Filtrate is concentrated, crude product is obtained, passes through column chromatography (DCM/MeOH=50:1 to 20:1) purify.TLC (DCM/MeOH=10 will be passed through:1,Rf=0.5) find that all fractions comprising product merge, and concentrate, Obtain brown solid the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl) aniline (1.4g, 4.09mmol, Yield 39.8%)：1H NMR (400MHz, methanol-d4) δ 7.31 (d, J=12.4Hz, 1H), 7.10 (d, J=8.8Hz, 1H), 3.51(s,2H),2.53(br.s.,8H),2.32-2.29(m,3H)；ES-LCMS m/z 292.1(M+H).
Intermediate 23：2- ((4- methoxy-benzyls) epoxide) -3- (2- methoxy ethoxies) -5- (tetra--first of 4,4,5,5- Base -1,3,2- dioxaborolan alkane -2- bases) pyridine
Step 1：The bromo- 2- chloropyridines -3- alcohol of 5-
At 100 DEG C, stirring the chloro- 3-Methoxy Pyridines of the bromo- 2- of 5- (36g, 162mmol) hydrobromic acid (200mL, Mixture in 3683mmol) 48 hours.Then, the mixture is concentrated, with the NaHCO of saturation3It is basified, and use EtOAc (600mL × 2) are extracted.By the organic extract of merging salt water washing, through Na2SO4It is dried, filtered and concentrated.Pass through silicagel column Chromatogram (PE/EtOAc=1：0~2：1) thick material is purified.TLC (PE/EtOAc=2 will be passed through：1,Rf=0.6) find comprising production All fractions of thing merge, and concentrate, and obtain 5- bromo- 2- chloropyridines -3- alcohol (21g, the 86mmol, yield of light yellow oil 52.9%)：1H NMR(400MHz,METHANOL-d4) δ 7.96 (t, J=2.0Hz, 1H), 7.47 (d, J=2.4Hz, 1H)；- ES-LCMS m/z 208.0,210.0(M+H)。
Step 2：The chloro- 3- of the bromo- 2- of 5- (2- methoxy ethoxies) pyridine
At 60 DEG C, in N2Under atmosphere, the bromo- 2- chloropyridines -3- alcohol (5g, 23.99mmol) of stirring 5-, the bromo- 2- methoxies of 1- Base-ethane (5.00g, 36.0mmol) and K2CO3The solution of (6.63g, 48.0mmol) in DMF (15mL) 16 hours.LCMS points Analysis shows that initial substance disappears.The mixture is filtered, and concentrates filtrate, crude product is obtained, passes through column chromatography (PE to PE/EA= 5/1) purify.TLC (PE/EA=5/1, R will be passed throughf=0.5) find that all fractions comprising product merge, and concentrate, obtain The bromo- 2- of 5- chloro- 3- (2- methoxy ethoxies) pyridine (5g, 18.39mmol, yield 77%) of white solid：1H NMR (400MHz,CHLOROFORM-d)δ8.07(s,1H),7.39-7.32(m,1H),4.21-4.18(m,2H),3.82-3.80(m, 2H), 3.47 (d, J=3.2Hz, 3H)；ES-LCMS m/z 265.9,267.9(M+H).
Step 3：The bromo- 2- of 5- ((4- methoxy-benzyls) epoxide) -3- (2- methoxy ethoxies) pyridine
At 0 DEG C, to the bromo- 2- of 5- chloro- 3- (2- methoxy ethoxies) pyridines (5.3g, 19.89mmol) at DMF (50mL) In solution in add 60%NaH (1.193g, 29.8mmol).After 0.5h, (4- methoxyphenyls) methanol is added (3.30g,23.86mmol).At 70 DEG C, obtained mixture is stirred 16 hours.Solvent is removed under vacuo.By residue point Fit between EA (60mL) and water (40mL), extracted with EtOAc (60mL × 2).Organic layer is washed with salt solution (40mL), through sulphur Sour sodium is dried, filtered and concentrated, and obtains crude product, passes through column chromatography (PE/EA=10:1 to 5:1) purify.TLC (PE/ will be passed through EA=5:1,Rf=0.5) find that all fractions comprising product merge, and concentrate, obtain 5- bromo- 2- ((the 4- first of yellow solid Oxy-benzyl) epoxide) -3- (2- methoxy ethoxies) pyridine (4.3g, 11.09mmol, yield 55.8%)：1H NMR (400MHz,METHANOL-d4) δ 7.76 (d, J=1.8Hz, 1H), 7.41 (d, J=2.0Hz, 1H), 7.37 (d, J=8.8Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 5.29 (s, 2H), 4.14-4.12 (m, 2H), 3.78 (s, 3H), 3.74-3.71 (m, 2H),3.38(s,3H)；ES-LCMS m/z 368.0,370.0(M+H).
Step 4：2- ((4- methoxy-benzyls) epoxide) -3- (2- methoxy ethoxies) -5- (4,4,5,5- tetramethyl -1, 3,2- dioxaborolan alkane -2- bases) pyridine
At 90 DEG C, in N2Under atmosphere, 5- bromo- 2- ((4- methoxy-benzyls) epoxide) -3- (2- methoxyl group ethoxies are stirred Base) pyridine (3g, 8.15mmol), 4,4,4', 4', 5,5,5', double (the 1,3,2- dioxaborolans of 5'- prestoxs -2,2'- Alkane) (2.276g, 8.96mmol), PdCl2(dppf) (0.596g, 0.815mmol) and potassium acetate (1.599g, 16.29mmol) Solution in 1,4- dioxanes (100mL) 2 hours.Lcms analysis shows that initial substance disappears.Filter the mixture.Concentration filter Liquid, obtains crude product, passes through column chromatography (PE/EA=10:1 to 5:1) purify.TLC (PE/EA=5/1, R will be passed throughf=0.45) It was found that all fractions comprising product merge, and concentrate, obtain 2- ((4- methoxy-benzyls) epoxide) -3- of light yellow solid (2- methoxy ethoxies) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (3.6g, 7.80mmol, yield 96%)：1H NMR(400MHz,METHANOL-d4) δ 8.03 (s, 1H), 7.43 (s, 1H), 7.37 (d, J= 8.4Hz, 2H), 6.88 (d, J=8.4Hz, 2H), 5.33 (s, 2H), 4.13-4.10 (m, 2H), 3.77 (s, 3H), 3.73-3.70 (m,2H),3.37(s,3H),1.33(s,12H)；ES-LCMS m/z 296.2(M+H-PMB).
Intermediate 24：4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) aniline
Step1：1- (5- fluoro- 2- (trifluoromethyl) phenyl)-N, N- dimethyl methylamines
Stir 2- (bromomethyl) -4- fluoro- 1- (trifluoromethyl) benzene (0.5g, 1.945mmol), dimethylamine hydrochloride (0.190g,2.334mmol)、Et3Mixtures of the N (0.597mL, 4.28mmol) in acetonitrile (20mL) is stayed overnight.Then, concentrate The mixture, obtains residue, is extracted with DCM (20mL × 2), through Na2SO4It is dried and concentrated, obtains the 1- (fluoro- 2- (trifluoros of 5- Methyl)-phenyl)-N, N- dimethyl methylamine (400mg, 1.808mmol, yield 93%)：1H NMR(400MHz,CD3OD)δ 7.71-7.75(m,1H),7.55-7.58(m,1H),7.15-7.19(m,1H),3.62(s,2H),2.29(s,6H)；ES-LCMS m/z 222(M+H)。
Step 2：1- (fluoro- 4- nitros -2- (trifluoromethyl) phenyl of 5-)-N, N- dimethyl methylamines
At 0 DEG C, to 1- (5- fluoro- 2- (trifluoromethyl) phenyl)-N, N- dimethyl methylamine (100mg, 0.452mmol) exists H2SO4Nitric acid (28.5mg, 0.452mmol) is added dropwise in mixture in (24.10 μ l, 0.452mmol).Stir the mixture 30 Minute, then, pour into ice/water.By the NaHCO of the mixture saturation3Solution is adjusted to pH=9, with DCM (20mL × 2) extract, through Na2SO4It is dried and concentrated, obtains 1- (fluoro- 4- nitros -2- (trifluoromethyl) phenyl of 5-)-N, N- dimethyl methylamines (100mg, 0.376mmol, yield 83%)：1H NMR(400MHz,CD3OD)δ7.62-7.64(m,1H),7.12-7.15(m, 1H),2.89(s,2H),1.52(s,6H)；ES-LCMS m/z 267(M+H).
Step 3：4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) aniline
To 1- (fluoro- 4- nitros -2- (trifluoromethyl) phenyl of 5-)-N, N- dimethyl methylamine (4.6g, 17.28mmol) and zinc NH is added in the mixture of (11.30g, 173mmol) in methanol (50mL)4Cl(9.24g,173mmol).At 15 DEG C, stir Mix the mixture 12 hours.The mixture is filtered, and concentrates filtrate, residue is obtained, is distributed in DCM (100mL) and H2O Between (50mL), extracted with DCM (100mL × 2).Organic extract is washed with salt solution (50mL), through Na2SO4Dry, filtering And concentrate, obtain 3.5g crude product.By preparing HPLC (instruments: DC/ posts: Gemini-C18 150*25mm*10ul/ flow Dynamic phase A: water (+ 0.1%HCl)/Mobile phase B: acetonitrile/gradient: 43-63B%)/flow velocity: 25ml/min/ run times: 15min) After purifying, 4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) aniline dihydrochloride of white-yellowish solid is obtained (560.65mg, 1.814mmol, yield 10.5%)：1H NMR (400MHz, MeOD-d4) δ 7.42 (d, J=11.6Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 4.34 (s, 2H), 2.88 (s, 6H)；ES-LCMS m/z 237.1(M+H).
Intermediate 25：(1- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl-propan -2- bases) t-butyl carbamate
Step 1：2,2- dimethyl -3- (2- (trifluoromethyl) phenyl) ethyl propionate
LDA is added dropwise to being cooled in mixture of -30 DEG C of the ethyl isobutyrate (37.9g, 326mmol) in THF (1L) (188mL,377mmol).At -30 DEG C, the mixture is stirred 1 hour.At -30 DEG C, 1- (bromine first is added into the mixture Base) solution of -2- (trifluoromethyl) benzene (60g, 251mmol) in THF (150mL).At -30 DEG C, whole mixture 1 is stirred Hour, then stirred 1 hour at 25 DEG C.Use NH4The mixture is quenched in Cl (aq, 200mL).Add this mixture to H2O In (200mL), and extracted with EtOAc (800mL × 3).Organic layer is washed with salt solution (800mL), through Na2SO4Dry, filtering And concentrate.In silica gel column chromatography (PE/EtOAc=200:1) thick material is purified on.TLC (PE/EtOAc=10 will be passed through:1,Rf =0.6) find that all fractions comprising product merge, and concentrate, obtain 2, the 2- dimethyl -3- (2- (trifluoros of light yellow solid Methyl) phenyl) ethyl propionate (57.5g, yield 83.2%)：1H NMR(400MHz,CDCl3) δ 7.62 (d, J=7.9Hz, 1H), 7.46-7.38 (m, 1H), 7.29 (t, J=7.6Hz, 1H), 7.22 (d, J=7.7Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 3.14 (s, 2H), 1.25 (t, J=7.2Hz, 3H), 1.17 (s, 6H).
Step 2：2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) ethyl propionate
To be cooled at 0 DEG C 2,2- dimethyl -3- (2- (trifluoromethyl) phenyl) ethyl propionate (115g, 419.1mmol) in H2SO4KNO is added portionwise in the solution of (500mL)3(44.4g, 440.8mmol).At 0 DEG C, stir this and mix Compound 30 minutes.The mixture is poured into ice-water (1.5L), and extracted with EtOAc (1L × 3).By the organic layer of merging With the Na of saturation2CO3Solution (1L × 3) is washed, through Na2SO4It is dried and concentrated, obtains 2, the 2- dimethyl -3- of brown oil (4- nitros -2- (trifluoromethyl) phenyl) ethyl propionate (120g, 376.1mmol, yield 89.5%)：1H NMR(400MHz, CDCl3) 8.53 (d, J=2.0Hz, 1H), 8.29 (dd, J=2.0,8.5Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 4.20 (q, J=7.0Hz, 2H), 3.25 (s, 2H), 1.27 (t, J=7.0Hz, 3H), 1.24-1.17 (m, 6H)；ES-LCMS m/z: 320(M+H)。
Step 3：2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionic acid
To 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl), (20g, 62.6mmol are in THF for ethyl propionate NaOH (39.2mL, 313mmol) is added in solution in (60mL).At 80 DEG C, the mixture is stirred 12 hours.Then, remove Remove THF.The pH of the mixture is adjusted to pH=1-2 with dense HCl.The mixture is extracted with DCM (30mL × 3).By organic phase Washed with water (20mL × 2) and salt solution (20mL), through Na2SO4It is dried, filtered and concentrated.By silica gel column chromatography (silica gel= 20g) (from PE/EtOAc=10:1 arrives PE/EtOAc=1：1) thick material is purified.TLC (PE/EtOAc=1 will be passed through：1,Rf= 0.3) find that all fractions comprising product merge, and concentrate, obtain 2, the 2- dimethyl -3- (4- nitros -2- of yellow solid (trifluoromethyl) phenyl) propionic acid (16.04g, 52.3mmol, yield 84%)：1H NMR(400MHz,CDCl3) δ 8.55 (d, J= 2.2Hz,1H),8.41-8.26(m,1H),7.70-7.54(m,1H),3.29(s,2H),1.28(s,6H)。
Step 4：2- methyl isophthalic acids-(4- nitros -2- (trifluoromethyl) phenyl) propyl- 2- amine
By Et3N (8.21mL, 58.9mmol) is added to 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) third In the solution of sour (16.04g, 55.1mmol) in toluene (160mL).At 0 DEG C, diphenyl phosphate azide is added (diphenyl phosphorazidate) (16.22g, 58.9mmol), and at 0 DEG C, stir the mixture 1 hour.20 At DEG C, the mixture is stirred for 1 hour, then stir mixture 3 hours at 100 DEG C.The solution is cooled down, and with water (3 × 50mL) washing, separation of methylbenzene phase, through Na2SO4Dry, and be evaporated in vacuo.Add 15% hydrochloric acid (36mL) and acetic acid The mixture of (36mL), and obtained mixture is stirred at 20 DEG C 12 hours.By mixture distribution in EtOAc (30mL) and Between water (40mL).With EtOAc (3 × 20mL) aqueous layer extracted.Then, water layer is adjusted to pH=9 with 2N NaOH, and use EtOAc (3 × 30mL) is extracted.The organic phase of merging is concentrated in a vacuum, obtains 2- methyl isophthalic acids-(4- nitros -2- (three of yellow oil Methyl fluoride) phenyl) propyl- 2- amine (8g, 27.5mmol, yield 49.9%)：1H NMR(400MHz,CDCl3) δ 8.55 (d, J= 1.8Hz, 1H), 8.33 (dd, J=1.8,8.4Hz, 1H), 8.03-7.86 (m, 1H), 3.00 (s, 2H), 1.18 (s, 6H)；ES- LCMS m/z 263.4(M+H)。
Step 5：(2- methyl isophthalic acids-(4- nitros -2- (trifluoromethyl)-phenyl)-propane -2- bases)-t-butyl carbamate
To 2- methyl isophthalic acids-(4- nitros -2- (trifluoromethyl) phenyl) propane -2- amine (6g, 22.88mmol) in THF In solution in (60mL) add sodium hydroxide (22.88mL, 45.8mmol) and di-tert-butyl dicarbonic acid ester (5.99g, 27.5mmol).At 20 DEG C, the mixture is stirred 12 hours.Then, by solution distribution in ethyl acetate (20mL) and water Between (40mL).With ethyl acetate (3 × 30mL) aqueous phase extracted.The organic extract of merging is washed with salt solution (40mL), passed through Na2SO4It is dried, filtered and concentrated, obtains (2- methyl isophthalic acids-(4- nitros -2- (trifluoromethyl) phenyl) propane -2- bases) amino first Tert-butyl acrylate (6.675g, 16.12mmol, yield 70.5%).TLC (PE/EtOAc=5:1,Rf=0.6):1H NMR (400MHz,CDCl3) δ 8.54 (s, 1H), 8.39-8.25 (m, 1H), 7.58 (d, J=8.4Hz, 1H), 3.40 (br.s., 2H), 1.51(s,9H),1.25(s,6H)；ES-LCMS m/z 307.3(M-t-Bu+H).
Step 6：(1- (4- amino -2- (trifluoromethyl) phenyl) -2- methylpropane -2- bases) t-butyl carbamate
To (2- methyl isophthalic acids-(4- nitros -2- (trifluoromethyl)-phenyl) propane -2- bases) t-butyl carbamate In the suspension of (6.675g, 18.42mmol) in methanol (60mL) add palladium carbon (10% aqueous solution, 0.196g, 1.842mmol).At 20 DEG C, in H2Under atmosphere (15Psi), the mixture is hydrogenated 5 hours.Then, the solution is filtered and dense Contracting, obtains (1- (4- amino -2- (trifluoromethyl) phenyl) -2- methylpropane -2- bases) tertiary fourth of carbamic acid of yellow oil Ester (4.5g, 8.53mmol, yield 46.3%)：TLC (PE/EA=1：1,Rf=0.4)；1H NMR(400MHz,CD3OD)δ7.78 (s, 1H), 7.51 (d, J=7.9Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 3.34 (s, 2H), 1.52 (s, 9H), 1.18 (br.s.,6H)。
Intermediate 26：3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzamide
Step 1：3- nitros -5- (trifluoromethyl) benzoic acid
Added into mixture of 3- (trifluoromethyl) benzoic acid (5g, 26.3mmol) in sulfuric acid (50ml, 938mmol) Nitric acid (3.53ml, 79mmol).At 0 DEG C, the mixture is stirred 15 minutes, and be warming up to 90 DEG C through 1 hour.Then, will The mixture is added drop-wise in frozen water.Then, the mixture is filtered, 3- nitros -5- (trifluoromethyl) benzene first of white solid is obtained Sour (5g, 20.20mmol, yield 77%)：1H NMR(400MHz,METHANOL-d4)δ8.99(s,1H),8.72(s,1H), 8.61(s,1H)。
Step 2：N- (2- (dimethylamino) ethyl) -3- nitros -5- (trifluoromethyl) benzamide
Add into mixture of 3- nitros -5- (trifluoromethyl) benzoic acid (500mg, 2.127mmol) in DCM (20mL) Enter N1,N1- dimethyl ethane -1,2- diamines (0.112mL, 2.339mmol), HATU (970mg, 2.55mmol) and DIEA (0.557mL,3.19mmol).At 25 DEG C, the mixture is stirred 16 hours.Then, the NaHCO of saturation is added3Solution (20mL).By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated, obtains N- (2- (dimethylaminos Base) ethyl) -3- nitros -5- (trifluoromethyl)-benzamide (400mg, 1.114mmol, yield 52.4%).TLC(DCM/ MeOH=15:1,Rf 0.4):1H NMR(400MHz,METHANOL-d4)δ8.98(s,1H),8.67(s,1H),8.59(s, 1H), 3.57 (t, J=6.5Hz, 2H), 2.60 (t, J=6.5Hz, 2H), 2.34-2.29 (m, 6H)；ES-LCMS m/z 306.1 (M+H)。
Step 3：3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzamide
To N- (2- (dimethylamino) ethyl) -3- nitros -5- (trifluoromethyl) benzamide (400mg, 1.310mmol) Pd/C (10%, 40mg) is added in mixture in methanol (20mL).At 25 DEG C, under hydrogen, the mixture 16 is stirred Hour.Then, filter the mixture and concentrate, obtain 3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzene Formamide (300mg, 0.926mmol, yield 70.7%).TLC (DCM/MeOH=10:1,Rf=0.2):1H NMR(400MHz, METHANOL-d4) δ 7.28 (d, J=10.8Hz, 2H), 7.03 (s, 1H), 3.50 (t, J=6.7Hz, 2H), 2.55 (t, J= 6.7Hz,2H),2.30(s,6H)；ES-LCMS m/z 276.1(M+H).
The preparation of the compound of the present invention
Embodiment 1：1- (the fluoro- 4- of 2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：(the fluoro- 4- of 3- (3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) ureas Base) phenyl) boric acid
To 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (6g, 11.76mmol), NH4OAc(2.72g, 35.3mmol) NaIO is added in the mixture in acetone (50ml) and water (50ml)4(7.54g,35.3mmol).Then, exist Mixture is stirred at 25 DEG C 12 hours.Then, the mixture is concentrated, residue is obtained, is extracted with DCM (20mL × 2).Will be organic Extract salt water washing, through Na2SO4It is dried, filtered and concentrated, obtains (the fluoro- 4- of 3- (3- (4- ((the 3- first of white-yellowish solid Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea groups) phenyl) boric acid (4.5g, 9.32mmol, yield 79%)：1H NMR(400MHz,CDCl3)δ8.12-8.08(m,1H),7.80(s,1H),7.57-7.44(br,3H),6.65- 6.63 (d, J=8.8Hz, 1H), 4.93-4.91 (d, J=6.4Hz, 2H), 4.66-4.64 (d, J=7.6Hz, 2H), 1.74 (s, 3H)；ES-LCMS m/z 429.1(M+H).
Step 2：(E) -3- (furans -3- bases) acrylic acid
Malonic acid is added into suspension of the furans -3- formaldehyde (2.3g, 23.94mmol) in pyridine (15mL) (2.74g,26.3mmol).Piperidines (0.204g, 2.394mmol) is added, and stirs at 100 DEG C the mixture 12 hours.So Afterwards, the mixture is cooled to room temperature.Then, the solution is poured into water (10mL), be acidified with 6M HCl.Diluted with EA The solution arrived.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Obtain (E) -3- (furans - 3- yls) acrylic acid (2.49g, 18.03mmol, yield 75%).TLC (PE/EA=5:1,Rf=0.6):1H NMR(400MHz, CD3OD) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.55-7.52 (d, J=12.8Hz, 1H), 6.73 (s, 1H), 6.20-6.16 (d, J=15.6Hz, 1H)；ES-LCMS m/z 139.0(M+H).
Step 3：(E) -3- (furans -3- bases) acryloyl group azide
Added into solution of (E) -3- (furans -3- bases) acrylic acid (2.49g, 18.03mmol) in THF (10mL) Et3N(2.189g,21.63mmol).DPPA (5.46g, 19.83mmol) is added, and it is small that the mixture is stood at 25 DEG C to 4 When.Then, by solution distribution in EA and the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, warp MgSO4It is dried, filtered and concentrated.MeOH debris is used, and is filtered, (E) -3- (furans -3- of light yellow solid are obtained Base) acryloyl group azide (3.46g, 21.21mmol, yield 118%)：1H NMR(400MHz,CDCl3)δ8.76(s, 1H),7.46(s,1H),4.16(s,3H)；1H NMR(400MHz,CD3Cl) δ 7.69 (s, 1H), 7.65-7.61 (d, J=16Hz, 1H), 7.43 (s, 1H), 6.58 (s, 1H), 6.15-6.11 (d, J=16Hz, 1H).
Step 4：Furans simultaneously [2,3-c] pyridine -7 (6H) -one
To (E) -3- (furans -3- bases) acryloyl group azide (3.46g, 21.21mmol) in 1,2- dichloro-benzenes I is added in solution in (31.2g, 212mmol)2(0.022g,0.085mmol).The mixture is stood at 180 DEG C to 2 small When.Then the solution is concentrated.Pass through silica gel column chromatography (PE/EA=1：1) residue is purified.TLC (DCM/MeOH=will be passed through 10:1,Rf=0.5) find that all fractions comprising product merge, and concentrate, obtain the furans of light yellow solid simultaneously [2,3-c] Pyridine -7 (6H) -one (765mg, 5.66mmol, yield 26.7%)：1H NMR(400MHz,CD3OD) δ 7.96-7.95 (d, J= 2.0Hz, 1H), 7.20-7.18 (d, J=6.8Hz, 1H), 6.84-6.83 (d, J=2.0Hz, 1H), 6.70-6.68 (d, J= 6.8Hz,1H)；ES-LCMS m/z 241(M+H).
Step 5：4- bromines furans simultaneously [2,3-c] pyridine -7 (6H) -one
Added into furans simultaneously solution of [2,3-c] pyridine -7 (6H) -one (20mg, 0.148mmol) in AcOH (5mL) Br2(7.63 μ L, 0.148mmol).The mixture is stood 2 hours at 25 DEG C.Then, solution is concentrated, and distributed in EA With the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated. To 4- bromines furans simultaneously [2,3-c] pyridine -7 (6H) -one (16mg, 0.075mmol, yield 50.5%).TLC (PE/EA=5:1,Rf =0.6):ES-LCMS m/z 214.9-215.9(M+H).
Step 6：1- (the fluoro- 4- of 2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
By (the fluoro- 4- of 3- (3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea groups) Phenyl) suspension of the boric acid (100mg, 0.234mmol) in 1,4- dioxanes (1.8mL) and water (0.600mL) is added to 4- Bromine furans simultaneously [2,3-c] pyridine -7 (6H) -one (50mg, 0.234mmol) in 1,4- dioxanes (1.8mL) and water (0.600mL) In solution in.Add PdCl2(dppf) (17.09mg, 0.023mmol) and Cs2CO3(190mg, 0.584mmol), and 110 At DEG C, the mixture is stirred under microwave 30 minutes.Then, the mixture is cooled to room temperature.Then, solution is concentrated, and Distribution is in EA and the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, through MgSO4Dry, filtering is simultaneously Concentration.By preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying residue, obtain the 1- (2- of yellow solid Fluoro- 4- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (4- ((3- methy oxetanes -3- Base) epoxide) -3- (trifluoromethyl) phenyl) urea (16.89mg, 0.033mmol, yield 13.97%)：1H NMR(400MHz, CD3OD)δ8.22-8.20(m,1H),8.06(s,1H),7.80(s,1H),7.56-7.53(m,1H),7.38-7.33(m,3H), 7.03 (s, 1H), 6.63-6.61 (d, J=8.8Hz, 1H), 4.90-4.88 (d, J=7.2Hz, 2H), 4.64-4.62 (d, J= 7.6Hz,2H),1.72(s,3H)；ES-LCMS m/z518.1(M+H).
Embodiment 2：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (3- (4- first Base -1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea
Step 1：The fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline
In N2It is lower to the bromo- 2- fluoroanilines (40g, 211mmol) of the 4- stirred at 20 DEG C, 4,4,4', 4', 5,5,5', 5'- Prestox -2,2'- double (1,3,2- dioxaborolans alkane) (64.1g, 253mmol) and KOAc (41.3g, 421mmol) exist It is disposable in solution in 1,4- dioxanes (500mL) to add PdCl2(dppf)(7.70g,10.53mmol).At 100 DEG C, Stirring reaction mixture 3 hours.Solution is concentrated under vacuum, the fluoro- 4- of 2- (4,4,5,5- tetramethyls -1,3,2- dioxas are obtained Boron heterocycle pentane -2- bases) aniline (44g, 158mmol, yield 74.9%)：1H NMR(400MHz,CDCl3)δ7.46-7.40(m, 2H), 6.75-6.71 (m, 1H), 1.30 (s, J=3.6Hz, 12H)；ES-LCMS m/z 238.1(M+H).
Step 2：4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines
To the bromo- 3- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (5g, 14.78mmol) in 1,4- dioxanes 5- bromo- 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyridine is added in mixture in (30mL) and water (10.0mL) (5g,14.78mmol)、Cs2CO3(9.63g, 29.6mmol) and PdCl2(dppf)(1.082g,1.478mmol).At 110 DEG C Under, in N2Lower stirring mixture 16 hours.Then, the reaction residue is filtered, and concentrates filtrate, passes through silica gel column chromatography (PE/EA=2/1) purify.TLC (PE/EA=8/1, R will be passed throughf=0.6) find that all fractions comprising product merge, and it is dense Contracting, obtain white solid 4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines (4g, 9.77mmol, yield 66.1%)：1H NMR(400MHz,CD3OD) δ 7.83 (d, J=2.0Hz, 1H), 7.40-7.37 (m, 2H), 7.34 (d, J=2.0Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.14 (m, 1H), 6.92-6.89 (m, 3H), 5.33 (s, 2H), 4.15-4.09 (m, 2H), 3.78 (s, 3H), 1.40 (t, J=7.2Hz, 3H)；ES-LCMS m/z 369.1(M+H).
Step 3：3- ethyoxyls -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- methoxy-benzyls) epoxide) pyridine
By 4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines (197mg, 0.535mmol) suspension in THF (10mL) is added to triphosgene (71.4mg, 0.241mmol) in THF (10mL) In solution.The mixture is stood 5 minutes at 60 DEG C.Then, the mixture is cooled to room temperature.Then, concentrate solution. To 3- ethyoxyls -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- methoxy-benzyls) epoxide) pyridine (200mg, 0.507mmol, yield 95%).TLC (PE/EA=5/1, Rf=0.5)：ES-LCMS m/z 307.1(M-87H).
Step 4：1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
By 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline (129mg, 0.535mmol) in THF Suspension in (10mL) is added to 3- ethyoxyls -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- methoxy-benzyls) epoxide) In solution of the pyridine (212mg, 0.535mmol) in THF (10mL).Add Et3N (0.186mL, 1.337mmol) and DMAP (6.53mg, 0.053mmol), and at 60 DEG C, stir the mixture 10 hours.The mixture is cooled to room temperature.Then, will Solution is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, through MgSO4 It is dried, filtered and concentrated.By preparing TLC (DCM/MeOH=20/1, Rf=residue 0.4) is purified, obtain light yellow solid 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (3- (4- methyl isophthalic acids H- Imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea (80mg, 0.126mmol, yield 23.53%)：1H NMR(400MHz, CD3OD)δ8.22(s,1H),8.18(s,1H),7.98(s,1H),7.91(s,1H),7.74(s,1H),7.49(s,1H), 7.49-7.37(m,6H),6.90-6.88(m,2H),5.33(s,2H),4.14-4.12(m,2H),3.78(s,3H),2.30(s, 3H), 1.42-1.39 (t, J=7.0Hz, 3H)；ES-LCMSm/z 636.0(M+H).
Step 5：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (3- (4- first Base -1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea
By 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (3- (4- Methyl-1 H-imidazole-1-group) -5- (trifluoromethyl) phenyl) suspension of the urea (80mg, 0.126mmol) in MeOH (10mL) It is added in solution of the Pd/C (26.8mg, 0.252mmol) (10%) in MeOH (10mL).At 26 DEG C, in H2Under atmosphere Hydrogenate the mixture 10 hours.Then, filter the solution and concentrate.By preparing HPLC (MeCN/H2O is used as eluent, alkalescence Condition) purifying residue, obtain 1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorobenzene of white solid Base) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea (14.40mg, 0.028mmol, yield 22.20%).TLC (DCM/MeOH=10/1, Rf=0.4):1H NMR(400MHz,CD3OD)δ8.16(s,1H),8.11-8.10 (d, J=1.6Hz, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.36-7.35 (m, 3H), 7.27 (s, 1H), 7.22 (s, 1H), 4.13-4.11 (m, 2H), 2.26 (s, 3H), 1.48-1.44 (t, J=7.0Hz, 3H)；ES-LCMS m/z 516.1(M+H)。
Embodiment 3：1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (1- oxo -2,5,6,7- tetrahydrochysenes - 1H- cyclopentas [c] pyridin-4-yl) phenyl) urea
Step 1：2- (2- ethyoxyl -2- oxoethyls) amyl- 1- olefinic carboxylic acids ethyl ester of ring
At 120 DEG C, stirring 2- (triphenylphosphanylidene) ethyl acetate (89g, 256mmol), 2- oxocyclopentanecarboxylic acids Mixture of the ethyl ester (40g, 256mmol) in toluene (300mL) 34 hours.Then, solvent is removed, and with EA (2 × 200mL) Extracted residues, the organic phase of merging is washed with salt solution (40mL), and through anhydrous Na2SO4Dry, filtering, and concentrate filtrate, Pass through post (PE:EA=20:1) residue is purified, obtains amyl- in 2- (2- ethyoxyl -2- oxoethyls) ring of yellow oil 1- olefinic carboxylic acids ethyl ester (15g, yield 23%)：1H NMR(400MHz,CDCl3)δ4.13(m,4H),3.66(s,2H),3.31(m, 2H),2.29(m,2H),1.84(m,2H),1.28(m,8H)；ES-LCMS m/z 227.1(M+H).
Step 2：1- oxo -1,5,6,7- tetrahydro cyclopentyl diene simultaneouslies [c] pyrans -4- carboxylic acid, ethyl esters
At 120 DEG C, stirring 2- (2- ethyoxyl -2- oxoethyls) amyl- 1- olefinic carboxylic acids ethyl ester of ring (7.5g, 33.1mmol), 1,1- dimethoxys-N, mixture 2 of the N- dimethyl methylamine (3.95g, 33.1mmol) in DMF (50mL) is small When, solvent is removed, and pass through post (PE:EA=5:1) residue is purified, 1- oxos -1,5 in yellow oil, 6,7- is obtained Tetrahydro cyclopentyl diene simultaneously [c] pyrans -4- carboxylic acid, ethyl esters (1.2g, yield 10.61%)：1H NMR(400MHz,CD3OD)δ4.18 (m,5H),1.88(m,2H),1.21(m,5H)；ES-LCMS m/z 209.1(M+H).
Step 3:2,5,6,7- tetrahydrochysene -1H- cyclopentas [c] pyridine -1- ketone
At 80 DEG C, stirring 1- oxos -1,5,6,7- tetrahydro cyclopentyl diene simultaneouslies [c] pyrans -4- carboxylic acid, ethyl esters (200mg, 0.961mmol), mixture of the ammoniacal liquor (0.208mL, 9.61mmol) in EtOH (1mL) 2 hours, concentrated solvent, and pass through system Standby TLC (DCM:MeOH=10:1) residue is purified, 2,5,6,7- tetrahydrochysene -1H- cyclopentas [c] pyridine -1- ketone are obtained (23mg, yield 16.67%)：1H NMR(400MHz,CD3OD) δ 7.25 (d, J=7.6Hz, 1H), 6.40 (d, J=6.4Hz, 1H),2.9-2.72(m,4H),2.06(m,2H)；ES-LCMS m/z 136.1(M+H).
Step 4：Bromo- 2,5,6,7- tetrahydrochysenes -1H- cyclopentas [c] pyridine -1- ketone of 4-
At 25 DEG C, 2,5,6,7- tetrahydrochysene -1H- cyclopentas [c] pyridine -1- ketone (34mg, 0.252mmol) of stirring, Mixture of the bromine (0.016mL, 0.302mmol) in AcOH (2mL) 1 hour.There is brown solid, remove solvent, and pass through Prepare TLC (DCM:MeOH=40:1) residue is purified, the tetrahydrochysene -1H- rings penta 2 of 4- bromo- 2,5,6,7- of brown solid are obtained Alkene simultaneously [c] pyridine -1- ketone (50mg, yield 91%)：1H NMR(400MHz,CD3OD)δ7.48(s,1H),2.94(m,4H), 2.15(m,2H)；ES-LCMS m/z 215.9(M+2H).
Step 5：4- (4- amino -3- fluorophenyls) -2,5,6,7- tetrahydrochysene -1H- cyclopentas [c] pyridine -1- ketone
At 90 DEG C, under microwave, 4- bromo- 2,5,6,7- tetrahydrochysene -1H- cyclopentas [c] pyridine -1- ketone is stirred (20mg, 0.093mmol), the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline (22.15mg,0.093mmol)、PdCl2(dppf)(6.84mg,9.34μmol)、K2CO3(25.8mg, 0.187mmol) is in 1,4- Mixture in dioxane (3mL) and water (1mL) 30 minutes.LCMS display reactions are completed, concentrated solvent, and by preparing TLC (DCM:MeOH=10:1) residue is purified, 4- (4- amino -3- fluorophenyls) -2,5,6,7- tetrahydrochysene -1H- cyclopentas are obtained [c] pyridine -1- ketone (11mg, yield 48.2%)：1H NMR(400MHz,CD3OD)δ7.27-7.25(m,1H),7.0-6.42(m, 3H),2.96-2.78(m,4H),2.08(m,2H)；ES-LCMS m/z 245.1(M+H).
Step 6：1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (1- oxo -2,5,6,7- tetrahydrochysenes - 1H- cyclopentas [c] pyridin-4-yl) phenyl) urea
At 60 DEG C, stirring 4- ethyoxyls -3- (trifluoromethyl) aniline (9.23mg, 0.045mmol), triphosgene The mixture of (6.01mg, 0.020mmol) in THF (3mL) 0.5 hour, LCMS display reactions are completed, and concentrated solvent is obtained 1- ethyoxyl -4- isocyanatos -2- (trifluoromethyl) benzene (10.1mg, 0.041mmol, yield 92%).At 60 DEG C, 1- is stirred Ethyoxyl -4- isocyanatos -2- (trifluoromethyl) benzene (10mg, 0.043mmol), 4- (4- amino -3- fluorophenyls) -2,5,6,7- Tetrahydrochysene -1H- cyclopentas [c] pyridine -1- ketone (10.57mg, 0.043mmol), Et3N (6.03 μ L, 0.043mmol) is in THF Mixture in (4mL) 30 minutes, concentrated solvent, and residue is purified by preparing HPLC, obtain 1- (4- ethyoxyls -3- (three Methyl fluoride) phenyl) -3- (the fluoro- 4- of 2- (1- oxos -2,5,6,7- tetrahydrochysene -1H- cyclopentas [c] pyridin-4-yl) phenyl) urea (5mg, yield 24.31%)：1H NMR(400MHz,CD3OD) δ 8.22 (t, J=8.80Hz, 1H), 7.75 (d, J=2.4Hz, 1H), 7.70 (s, 1H), 7.55 (m, 1H), 7.30 (d, J=12Hz, 1H), 7.23 (d, J=7.2Hz, 1H), 7.12 (d, J= 8.8Hz, 1H), 4.14 (t, J=6.8Hz, 2H), 3.10 (t, J=7.6Hz, 2H), 2.97 (t, J=7.6Hz, 2H), 2.19 (m, 2H), 1.39 (t, J=7.2Hz, 3H)；ES-LCMS m/z476.1(M+H).
Embodiment 4：1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydro-1 h-pyrazoles simultaneously [4,3-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：Chloro- 1H- pyrazolos [4,3-c] pyridines of 4-
At 80 DEG C, stirring 2,4- dichloro nicotine aldehyde (800mg, 4.55mmol) and hydrazine (364mg, 9.09mmol) are in DME Mixture in (10mL) 2 hours, concentrates the solvent, and pass through column chromatography (DCM：MeOH=20:1,800mL) purify remaining Thing, obtains chloro- 1H- pyrazolos [4, the 3-c] pyridines (400mg, 2.474mmol, yield 54.4%) of 4-：1H NMR(400MHz, CDCl3) δ 13.85 (m, 1H), 8.31 (s, 1H), 8.13 (d, J=5.6Hz, 1H), 7.60 (d, J=5.6Hz, 1H)；ES-LCMS m/z 154.0(M+H)。
Step 2：1H- pyrazolos [4,3-c] pyridine -4 (5H) -one
At 100 DEG C, stirring 4- chloro- 1H- pyrazolos [4,3-c] pyridines (400mg, 2.60mmol), AcOH (29.8mL, 521mmol) and water (0.1mL) mixture 8 hours, LCMS display reactions complete, and concentrated solvent obtains 1H- pyrazolos [4,3- C] pyridine -4- alcohol (300mg, 2.027mmol, yield 78%)：1H NMR(400MHz,CDCl3)δ10.87(m,1H),8.06(s, 1H), 7.11 (d, J=6.8Hz, 2H), 6.42 (d, J=6.8Hz, 2H).
Step 3：Bromo- 1H- pyrazolos [4,3-c] pyridine -4 (5H) -one of 7-
At 30 DEG C, stirring 1H- pyrazolos [4,3-c] pyridine -4 (5H) -one (80mg, 0.592mmol), Br2 The mixture of (0.031mL, 0.592mmol) in AcOH (5mL) 8 hours, concentrated solvent, and it is remaining by preparing HPLC purifying Thing, obtains bromo- 1H- pyrazolos [4,3-c] pyridine -4 (5H) -one (65mg, 0.301mmol, yield 50.8%) of 7-：1H NMR (400MHz,DMSO)δ13.2-12.9(m,1H),10.4-10.0(m,1H),7.7-7.3(m,1H),6.57-6.42(m,1H)； ES-LCMS m/z 214.0,216.0(M+H)。
Step 4：1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydro-1 h-pyrazoles simultaneously [4,3-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
At 120 DEG C, under microwave, bromo- 1H- pyrazolos [4,3-c] pyridine -4 (5H) -one of stirring 7- (20mg, 0.093mmol), 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (40.0mg, 0.093mmol), PdCl2 (dppf)-DCM adducts (7.63mg, 9.34 μm of ol), K2CO3(25.8mg, 0.187mmol) is in DMF (2mL) and water (0.2mL) In mixture 130 minutes, concentrated solvent, and by preparing TLC (DCM:MeOH=10:1,Rf=residue 0.35) is purified, Then by preparing HPLC purifying, 1- (the fluoro- 4- of 2- (4- oxos -4,5- dihydro-1 h-pyrazole simultaneously [4,3-c] pyridine -7- are obtained Base) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (1.33mg, 2.480 μ Mol, yield 2.65%)：1H NMR(400MHz,CD3OD+DMSO-d6) δ 8.49-8.21 (m, 2H), 7.84 (d, J=2.8Hz, 1H), 7.57-7.53 (m, 3H), 7.31 (s, 1H), 6.65 (d, J=8.8Hz, 1H), 4.91 (m, 2H), 4.64 (m, 2H), 1.72 (s,1H)；ES-LCMS m/z 518.1(M+H).
Embodiment 5：1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea
Step 1：5- amino -5'- ethyoxyl -6- methyl-[2,3'- bipyridyls] -6'(1'H) -one
At 25 DEG C, in H2Under atmosphere, the pyrrole of stirring 6'- (benzyloxy) -5'- ethyoxyl -6- methyl-5-nitros -2,3'- bis- The mixture of pyridine (150mg, 0.411mmol) and Pd/C (2.184mg, 0.021mmol) in MeOH (10mL) 1 hour.Then, The mixture is concentrated, residue is obtained, is extracted with DCM (20mL × 2).By organic extract salt water washing, through Na2SO4It is dry It is dry, filter and concentrate.By preparing TLC (EA：PE=1：1) purify residue, obtain 5- amino -5'- ethyoxyl -6- methyl - [2,3'- bipyridyls] -6'(1'H) -one (80mg, 0.245mmol, yield 59.6%)：1H NMR(400MHz,CD3OD)δ7.46 (d, J=2.00Hz, 1H), 7.42 (d, J=2.00Hz, 1H), 7.30-7.28 (m, 1H), 7.07-7.05 (d, J=8.40Hz, 1H),4.14-4.08(m,2H)；2.38 (s, 3H), 1.45 (t, J=7.00Hz, 3H)；ES-LCMS m/z 246(M+H).
Step 2：4- isocyanato -1- isopropoxies -2- (trifluoromethyl) benzene
It is mixed in THF (10mL) to 4- isopropoxies -3- (trifluoromethyl) anilinechloride (70mg, 0.274mmol) Et is added in compound3N(0.038mL,0.274mmol).Then, 60 DEG C are heated the mixture to 30 minutes, concentrate the mixture, Obtain 4- isocyanato -1- isopropoxies -2- (trifluoromethyl) benzene (60mg, 0.224mmol, yield 82%)：ES-LCMS m/z 278(M+33)。
Step 3：1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea
To 5- amino -5'- ethyoxyl -6- methyl-[2,3'- bipyridyls] -6'(1'H) -one (60mg, 0.245mmol) and In mixture of 4- isocyanato -1- isopropoxies -2- (trifluoromethyl) benzene (60.0mg, 0.245mmol) in THF (10mL) Add Et3N(0.102mL,0.734mmol).Then, heating mixture to 60 DEG C 30 minutes, concentrate the mixture, then pass through Prepare HPLC purifying, obtain the 1- (5'- ethyoxyl -6'- hydroxyl -6- methyl-[2,3'- bipyridyl] -5- bases) of light yellow solid - 3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea hydrochloride (54.09mg, 0.102mmol, yield 41.6%)：1H NMR (400MHz,CD3OD) δ 8.83 (m, 1H), 7.93 (s, 1H), 7.79-7.73 (d, J=11.2Hz, 1H), 7.59 (t, J= 5.80Hz, 1H), 7.44 (s, 1H), 7.20-7.17 (d, J=8.80Hz, 1H), 4.72 (t, J=6.20Hz, 1H), 4.17 (t, J =7.00Hz, 2H), 2.77-2.75 (d, J=8.00Hz, 3H), 1.51 (t, J=7.00Hz, 3H), 1.36-1.34 (d, J= 6.00Hz,6H)；ES-LCMS m/z 491(M+H).
Embodiment 6：1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (5'- ethyoxyl -6- methyl -6'- oxos - 1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) urea
Step 1：3- (difluoromethyl) -4- isopropoxy anilines
At 25 DEG C, stirring 2- (difluoromethyl) -1- isopropoxy -4- nitrobenzene (200mg, 0.865mmol), NH4Cl The mixture of (463mg, 8.65mmol) and zinc (566mg, 8.65mmol) in MeOH (20mL) 2 hours.The mixture is used DCM (200mL × 2) is extracted, through Na2SO4Be dried and concentrated, obtain 3- (difluoromethyl) -4- isopropoxy anilines (150mg, 0.482mmol, yield 55.7%)：1H NMR(400MHz,CD3OD) δ 6.90-6.80 (m, 3H), 6.85 (t, J=56.00Hz, 1H), 4.50-4.38 (m, 1H), 1.26-1.25 (d, J=6.00Hz, 1H)；ES-LCMS m/z 202(M+H).
Step 2：2- (difluoromethyl) -4- isocyanato -1- isopropoxy benzenes
Into mixture of 3- (the difluoromethyl) -4- isopropoxy anilines (200mg, 0.994mmol) in THF (10mL) Add triphosgene (118mg, 0.398mmol).Then, 60 DEG C are heated the mixture to 30 minutes, concentrates the mixture, obtain 4- Cyanato -2- (difluoromethyl) -1- isopropoxy benzenes (210mg, 0.620mmol, yield 62.4%)；ES-LCMS m/z 260 (M+33)。
Step 3：1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (5'- ethyoxyl -6- methyl -6'- oxo -1', 6'- dihydros-[2,3'- bipyridyls] -5- bases) urea
To 5- amino -5'- ethyoxyl -6- methyl-[2,3'- bipyridyls] -6'(1'H) -one (100mg, 0.408mmol), Added in mixture of 4- cyanatos -2- (the difluoromethyl) -1- isopropoxy benzenes (93mg, 0.408mmol) in THF (10mL) Et3N(0.114mL,0.815mmol).Then, 60 DEG C are heated the mixture to 30 minutes, concentrated, it is then pure by preparing HPLC Change, obtain yellow solid 1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (5'- ethyoxyl -6- methyl -6'- oxos - 1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) urea hydrochloride (16.72mg, 0.032mmol, yield 7.80%)：1HNMR (400MHz,CD3OD) δ 8.71-8.69 (d, J=8.40Hz, 1H), 7.85-7.82 (d, J=9.20Hz, 1H), 7.68 (d, J= 2.00Hz, 1H), 7.52-7.49 (m, 1H), 7.43 (d, J=2.40,1H), 7.07 (d, J=1.60Hz, 1H), 6.93 (t, J= 52.0Hz, 1H), 4.66-4.60 (m, 2H), 4.17-4.12 (m, 3H), 2.69 (s, 3H), 1.47 (t, J=7.00Hz, 3H), (1.33-1.31 d, J=6.00Hz, 6H)；ES-LCMS m/z 473(M+H).
Embodiment 7：1- (the fluoro- 4- of 2- (5- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The fluoro- 4- of 2- (6- methoxyl group -5- picoline -3- bases) aniline
To (6- methoxyl group -5- picoline -3- bases) boric acid (300mg, 1.797mmol), the bromo- 2- fluoroanilines of 4- Cs is added in the mixture of (341mg, 1.797mmol) in water (3mL) and 1,4- dioxanes (9mL)2CO3(1171mg, 3.59mmol) and PdCl2(dppf)(65.7mg,0.090mmol).Then, at 100 DEG C, the mixture is stirred 3 hours.It is dense Contract the mixture, obtains residue, is dissolved in EA and water, extracted with EA, obtains organic layer.Concentration of organic layers, obtains residual Excess.By silica gel chromatography residue, obtain in yellow oil the fluoro- 4- of 2- (6- methoxyl group -5- picolines - 3- yls) aniline (320mg, 1.378mmol, yield 77%).1H NMR(400MHz,CDCl3) δ 8.12 (d, J=2.8Hz 1H), 7.51 (s, 1H), 7.17 (dd, J=2.0Hz and 12Hz, 1H), 7.19 (dd, J=2.0Hz and 12Hz, 1H), 6.84 (dd, J=9.2Hz and 8.0Hz, 1H) 3.97 (s, 3H), 2.75 (s, 2H), 2.22 (s, 3H), ES-LCMS m/z 233.1 (M+H)。
Step 2：5- (4- amino -3- fluorophenyls) -3- picolines -2 (1H) -one
At 100 DEG C, in N2Under, stirring 2- fluoro- 4- (6- methoxyl group -5- picoline -3- bases) aniline (170mg, 0.732mmol) in HBr/H2Solution in O (10mL) 16 hours.Concentrated reaction mixture, obtains residue, and by residue It is dissolved in EA.By the NaHCO of organic phase saturation3Solution (10mL), water (10mL) and salt solution (10mL) washing, through Na2SO4It is dry It is dry, and be evaporated in vacuo, obtain 5- (4- amino -3- fluorophenyls) -3- picolines -2 (1H) -one in yellow solid (120mg, 0.550mmol, yield 75%).1H NMR(400MHz,CD3OD) δ 8.01 (d, J=6Hz 1H), 7.86 (d, J= 6Hz 1H) 7.71 (d, J=12Hz, 1H), 7.60 (m, 2H), 2.26 (s, 3H), ES-LCMS m/z 219.1 (M+H).
Step 3：1- (the fluoro- 4- of 2- (5- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To at room temperature, in N24- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene of lower stirring Triphosgene (24.01mg, 0.081mmol) is added in solution of the amine (50mg, 0.202mmol) in THF (10mL).At 50 DEG C Under, stir the mixture 40 minutes.5- (4- amino -3- fluorophenyls) -3- picolines -2 (1H) -one is added into mixture (44.1mg, 0.202mmol) and Et3N(0.085mL,0.607mmol).At 50 DEG C, the mixture is stirred 4 hours, then, Purified by HPLC, obtain 1- (the fluoro- 4- of 2- (5- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (26mg, 0.052mmol, yield 25.9%)：1H NMR (400MHz,CD3OD) δ 8.17 (t, J=8.4Hz 1H), 7.86 (dd, J=1.6Hz and 8Hz 2H) 7.59 (m, 2H), 7.40 (m, 2H), 6.66 (d, J=8Hz 1H), ES-LCMS m/z 492.1 (M+H).
Embodiment 8：1- (5'- ethyoxyl -2- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 6- picolines -2- amine of 5-
At 0 DEG C, in N2Under, solution of the stirring 6- picoline -2- amine (5g, 46.2mmol) in MeOH (20mL).Will NBS (8.23g, 46.2mmol) is slowly added in solution, at 0 DEG C, stirring reaction mixture 1 hour.At room temperature, stir Mix reactant mixture 16 hours.Then, the solution is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution.By merging Organic extract salt water washing, through MgSO4It is dried, filtered and concentrated.By silica gel chromatography residue, 5- is obtained Bromo- 6- picolines -2- amine (3g, 16.04mmol, yield 34.7%).1H NMR(400MHz,CD3OD) δ 7.49 (d, J= 8.8Hz, 1H), 6.33 (d, J=8.8Hz, 1H), 2.39 (s, 3H), ES-LCMS m/z 188.9 (M+H).
Step 2：4- isopropoxies -3- (trifluoromethyl) aniline
At 30 DEG C, in H21- isopropoxy -4- nitros -2- (trifluoromethyl) benzene (2g, 8.03mmol) is stirred under atmosphere With suspension of the Pd/C (0.2g, 1.879mmol) in MeOH (30mL).At 30 DEG C, stirring reaction mixture 4 hours.Cross The reactant mixture is filtered, and concentrates filtrate, 4- isopropoxies -3- (trifluoromethyl) aniline (1.8g, 7.06mmol, yield is obtained 88%).1H NMR(400MHz,CDCl3) δ 7.84 (m, 2H), 6.90 (t, J=2.8Hz, 1H), 6.85 (s, 1H), 6.79 (t, J =2.8Hz, 1H), 4.52-4.43 (m, 1H), 2.60 (s, 3H), 1.32 (d, J=2.8Hz, 6H)-；ES-LCMS m/z 220.0 (M+H)。
Step 3：1- (the bromo- 6- picolines -2- bases of 5-) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea
At 60 DEG C, in N2Under atmosphere, the stirring bromo- 6- picolines -2- amine (1g, 5.35mmol) of 5- and triphosgene The solution of (0.714g, 2.406mmol) in THF (20mL).At 60 DEG C, stirring reaction mixture 15 minutes.By Et3N and 4- isopropoxies -3- (trifluoromethyl) aniline (1.172g, 5.35mmol) is added in reactant mixture.At 60 DEG C, stirring The reactant mixture 16 hours.Then, the solution is cooled to room temperature, and viaBedding and padding are filtered, and obtaining 11-, (5- is bromo- 6- picoline -2- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea (500mg, 1.157mmol, yield 21.64%)；1H NMR(400MHz,CD3OD) δ 7.84 (m, 2H), 7.59 (dd, J=9.6Hz, J=2.8Hz, 1H), 7.16 (d, J=9.2Hz, 1H), 7.01 (d, J=8.8Hz, 1H), 4.72 (m, 1H), 2.60 (s, 3H), 1.30 (s, 6H) .ES-LCMS m/z 432.0(M+H)。
Step 4：1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -2- methyl-[3,3'- bipyridyls] -6- Base) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea
In N2Under, stir Cs2CO3(0.846g,2.60mmol)、PdCl2(dppf) (0.095g, 0.130mmol), 3- second Epoxide -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyrrole Pyridine (1g, 2.60mmol) and 1- (the bromo- 2- fluorophenyls of 4-) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea (1.130g, The 2.60mmol) solution in dioxanes/water (20mL).At 120 DEG C, the reactant mixture is stirred 16 hours.Then, concentrate The solution, and pass through silica gel column chromatography (PE/EA=3:1) residue is purified, 1- (5'- ethyoxyls -6'- ((4- methoxyl groups are obtained Benzyl) epoxide) -2- methyl-[3,3'- bipyridyls] -6- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea (400mg, 0.652mmol, yield 25.1%)；1H NMR(400MHz,CD3OD) δ 7.65 (d, J=2Hz, 1H), 7.62 (m, 3H), 7.41 (d, J=8.4Hz, 2H), 7.22 (d, J=2Hz, 1H), 7.17 (d, J=9.2Hz, 1H), 7.04 (d, J= 8.4Hz, 1H), 6.92 (d, J=8.4Hz, 2H), 5.36 (s, 2H), 4.70 (m, 1H), 4.09 (m, 2H), 3.79 (s, 3H), (s, 6H) the .ES-LCMS m/z 611.1 (M+H) of 3.14 (d, J=2Hz, 3H), 1.44 (s, 3H), 1.20.
Step 5：1- (5'- ethyoxyl -2- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, in N2Under, stirring 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -2- methyl-[3, 3'- bipyridyls] -6- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea (400mg, 0.655mmol) is in TFA:DCM Solution in (20mL).At 25 DEG C, stirring reaction mixture 2 hours.Concentrated reaction mixture in a vacuum.By preparing HPLC(MeCN/H2O is used as eluent, acid condition) purifying residue, obtain 1- (5'- ethyoxyl -2- methyl -6'- oxos - 1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea (34.63mg, 0.071mmol, yield 10.78%),1H NMR(400MHz,CD3OH) δ 7.84 (d, J=2.4Hz, 1H), 7.60 (m, 2H), 7.17 (d, J=9.2Hz, 1H), 7.03 (d, J=8.4Hz, 1H), 6.98 (dd, J=7.6Hz, J=2.0Hz2H), 4.57 (s, 1H), 4.15 (m, 2H), 2.52 (s, 3H), 1.45 (t, J=6.8Hz, 3H), 1.33 (d, J=6.0Hz, 3H), ES-LCMS m/z 491.2(M+H)。
Embodiment 9：1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
Step 1：3- (4- isocyanatos -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls
To 3- (4- amino -2- (trifluoromethyl) phenyl) -2,2- dimethyl propylenes acid esters (300mg, 1.037mmol) in THF Triphosgene (108mg, 0.363mmol) is added portionwise in solution in (30mL).At 60 DEG C, the mixture and backflow 30 are stirred Minute.After lcms analysis shows that initial substance disappears.Reaction solution is evaporated, 3- (4- isocyanato -2- (trifluoros are obtained Methyl) phenyl) -2,2- ethyl dimethyls (250mg, 0.725mmol, yield 69.9%)：ES-LCMS m/z 348.1(M +MeOH)。
Step 2：3- (4- (3- (the bromo- 3- picolines -2- bases of 5-) urea groups) -2- (trifluoromethyl) phenyl) -2,2- diformazans Base ethyl propionate
To 2- ((3- (4- isocyanatos -2- (trifluoromethyl) phenyl) -2,2- Dimethylpropanoyls) epoxide) ethane -1- bases Solution of the bromo- 3- picolines -2- amine (149mg, 0.795mmol) of (250mg, 0.795mmol), 5- in THF (30mL) Middle addition DMAP (194mg, 1.591mmol) and Et3N(0.222mL,1.591mmol).At 60 DEG C, the mixture 3 is stirred small When.After lcms analysis shows that initial substance disappears, with EA (40mL) extractive reaction mixture, and with water (15mL) and salt solution (15mL) washs organic layer.Organic phase is evaporated, and by preparing TLC (PE/EA=1/1, Rf=residue 0.4) is purified, obtain To pure products 3- (4- (3- (the bromo- 3- picolines -2- bases of 5-) urea groups) -2- (trifluoromethyl) phenyl) -2,2- neopentanoic acids Ethyl ester (200mg, 0.262mmol, yield 32.9%)：1HNMR(400MHz,CDCl3) δ 8.32 (d, J=2.4Hz, 1H), 8.03 (d, J=2.4Hz, 1H), 7.81 (d, J=1.6Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.24 (d, J=5.6Hz, 1H), 4.17 (d, J=7.2Hz, 2H), 3.10 (s, 2H), 2.32 (s, 3H), 1.26 (s, 3H), 1.18 (s, 6H)；ES-LCMS m/z 502.1(M+H)。
Step 3：3- (4- (3- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -5- methyl-[3,3'- joins pyrrole Pyridine] -6- bases) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls
There to be 2- ((3- (4- (3- (the bromo- 3- picolines -2- bases of 5-) urea groups) -2- (trifluoromethyl) phenyl) -2,2- Dimethylpropanoyl) epoxide) ethane -1- bases (100mg, 0.199mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) oxygen Base) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (77mg, 0.199mmol), PdCl2 (dppf) (14.60mg, 0.020mmol) and Cs2CO3(195mg, 0.598mmol) is in 1,4- dioxanes (3ml) and water (1ml) Solution reaction vessel sealing, and in microwave at 110 DEG C heat 20 minutes.Show and observed correctly in lcms analysis After product, reaction solution is evaporated, and with DCM (40mL) extracted residues, uses H2O (15mL) and salt solution (15mL) washing. Through Na2SO4Organic layer is dried, filters and concentrates.By preparing TLC (DCM/MeOH=20/1, Rf=residue 0.45) is purified, Obtain pure products 2- ((3- (4- (3- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -5- methyl-[3,3'- connection pyrroles Pyridine] -6- bases) urea groups) -2- (trifluoromethyl) phenyl) -2,2- Dimethylpropanoyls) epoxide) ethane -1- bases (50mg, 0.067mmol, yield 33.6%)：1H NMR(400MHz,DMSO-d6)δ8.88(br.s.,1H),8.59(s,1H),8.02- 8.07 (m, 2H), 7.74 (d, J=8.4Hz, 1H), 7.60 (d, J=1.8Hz, 1H), 7.41 (d, J=8.8Hz, 2H), 7.23 (d, J=8.4Hz, 1H), 6.95 (d, J=8.8Hz, 2H), 5.34 (s, 2H), 4.06-4.21 (m, 4H), 3.76 (s, 3H), 3.01 (s, 2H), 2.36 (s, 3H), 1.35 (t, J=7.0Hz, 3H), 1.08-1.31 (m, 9H)；ES-LCMS m/z 681.2(M +H)。
Step 4：1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -5- methyl-[3,3'- bipyridyls] -6- Base) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
To 3- (4- (3- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -5- methyl-[3,3'- bipyridyls] -6- Base) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (50mg, 0.073mmol) are in THF (10mL) LAH (8.36mg, 0.220mmol) is added portionwise in solution.At 0 DEG C, the mixture is stirred 1 hour.Shown in lcms analysis After initial substance disappears, reaction solution is quenched with water (2mL), NaOH (6mL) and water (2mL).Then, extracted with DCM (30mL) The mixture is taken, and is washed with salt solution (10mL).Through Na2SO4Organic layer is dried, filters and concentrates.By preparing TLC (DCM/ MeOH=40/1, Rf=residue 0.54) is purified, obtain pure products 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) oxygen Base) -5- methyl-[3,3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) Urea (40mg, 0.047mmol, yield 63.6%)：1H NMR(400MHz,CD3OD)δ8.50(s,1H),8.02-7.95(m,2H), 7.91 (br.s., 1H), 7.70 (d, J=8.6Hz, 1H), 7.50-7.44 (m, 2H), 7.41 (d, J=8.6Hz, 2H), 6.92 (d, J=8.8Hz, 2H), 5.38 (s, 2H), 4.60 (s, 2H), 4.17 (q, J=7.0Hz, 2H), 3.82-3.76 (m, 3H), 2.80 (s, 2H), 2.40 (s, 3H), 1.44 (t, J=7.0Hz, 3H), 0.86 (s, 6H)；ES-LCMS m/z 639.2(M+H).
Step 5：1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
At 20 DEG C, stir in HCl 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -5- methyl-[3, 3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea (20mg, 0.031mmol) the solution in MeOH (8mL, 32.0mmol) 30 minutes.After lcms analysis shows that initial substance disappears, Reactant mixture is evaporated, and by preparing HPLC (instruments: DB/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1% HCl/ Mobile phase Bs:MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：40-60 (B%)) purifying, obtain white-yellowish solid 1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyls -2,2- Dimethyl propyl) -3- (trifluoromethyl) phenyl) urea (7.36mg, 0.014mmol, yield 44.1%)：1H NMR(400MHz, CD3OD) δ 8.50 (s, 1H), 8.37 (d, J=2.0Hz, 1H), 8.03 (d, J=2.0Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.52 (d, J=8.4Hz, 1H), 7.47 (d, J=2.4Hz, 1H), 7.25 (d, J=2.2Hz, 1H), 4.18-4.136 (m, 2H), 3.32 (br.s., 2H), 2.82 (s, 2H), 2.54 (s, 3H), 1.49 (t, J=7.0Hz, 3H), 0.86 (s, 6H)；ES- LCMS m/z 519.1(M+H)。
Embodiment 10：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- hydroxyethyls) -3- (trifluoromethyl) phenyl) urea
Step 1：The chloro- 5- isocyanatos -4- methylpyrimidines of 2-
Disposably add into solution of the chloro- 4- methylpyrimidines -5- amine (300mg, 2.090mmol) of 2- in THF (20mL) Enter triphosgene (620mg, 2.090mmol).At 60 DEG C, the mixture is stirred 20 minutes.Lcms analysis shows that initial substance disappears Lose：ES-LCMS m/z 202.1(M+MeOH).
Step 2：1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea
To 1- (4- amino -2- (trifluoromethyl) phenyl) solution of the ethyl ketone (419mg, 2.064mmol) in THF (20mL) Middle addition DMAP (126mg, 1.032mmol), Et3The chloro- 5- isocyanatos -4- methyl of N (0.863mL, 6.19mmol) and 2- is phonetic Solution of the pyridine (350mg, 2.064mmol) in THF (5mL).At 60 DEG C, the mixture is stirred at reflux 1 hour.At LCMS points After analysis shows that initial substance disappears.Reaction solution is extracted with DCM (60mL), and uses H2O (20mL) and salt solution (20mL) are washed Wash.Through Na2SO4Organic layer is dried, filters and concentrates.Residue is purified by silica gel column chromatography (PE/EA=2/1 to 1/2), obtained To pure products 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea (300mg, 0.757mmol, yield 36.7%)：1H NMR(400MHz,CD3OD)δ9.05(s,1H),7.97(s,1H),7.77-7.71(m, 2H),2.55(s,3H),2.51(s,3H)；ES-LCMS m/z 373.0(M+H).
Step 3：1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) Epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
In microwave, at 110 DEG C, (the chloro- 4- methyl of 2- is phonetic by -3- by stirring 1- (4- acetyl group -3- (trifluoromethyl) phenyl) Pyridine -5- bases) urea (200mg, 0.537mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolan alkane -2- bases) pyridine (207mg, 0.537mmol), PdCl2(dppf)(39.3mg, 0.054mmol) and Cs2CO3The solution of (524mg, 1.610mmol) in 1,4- dioxanes (3mL) and water (1mL) 20 minutes. Lcms analysis is shown it was observed that after correct material.Reaction solution is evaporated, extracted with DCM (40mL), and use H2O(10mL) With salt solution (10mL) washing.By preparing TLC (DCM/MeOH=20/1, Rf=residue 0.52) is purified, obtain given product 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea (250mg, 0.243mmol, yield 45.4%)：1H NMR(400MHz,CD3OD)δ9.09 (s, 1H), 8.66 (d, J=2.0Hz, 1H), 8.06 (d, J=1.6Hz, 1H), 7.98 (s, 1H), 7.74 (d, J=2.0Hz, 1H), 7.71 (s, 1H), 7.39 (d, J=8.8Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 5.36 (s, 2H), 4.17-4.12 (m, 2H), 3.77 (s, 3H), 2.56 (s, 3H), 2.54 (s, 3H), 1.42 (t, J=7.0Hz, 3H)；ES-LCMS m/z 476.1 (M-PMB+H),596.1(M+H)。
Step 4：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (4- (1- hydroxyethyls) -3- (trifluoromethyl) phenyl) urea
To 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) Pyridin-3-yl) -4- methylpyrimidine -5- bases) it is added portionwise in solution of the urea (140mg, 0.235mmol) in THF (5mL) NaBH4(44.5mg,1.175mmol).At 20 DEG C, the mixture is stirred 3 hours.Show that initial substance disappears in lcms analysis Afterwards.Water (10mL) is added dropwise reaction solution is quenched.The mixture is extracted with EA (30mL), and is washed with salt solution (10mL).Through Na2SO4Organic layer is dried, filters and concentrates.By preparing TLC (DCM/MeOH=20/1, Rf=residue 0.56) is purified, obtain To product 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- (1- hydroxyethyls) -3- (trifluoromethyl) phenyl) urea (100mg, 0.100mmol, yield 42.7%)：1H NMR(400MHz, CD3OD) δ 9.10 (s, 1H), 8.67 (d, J=1.8Hz, 1H), 8.08 (d, J=1.8Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.65 (d, J=8.8Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 6.91 (d, J= 8.8Hz, 2H), 5.38 (s, 2H), 5.16 (d, J=6.0Hz, 1H), 4.18-4.13 (m, 2H), 3.78 (s, 3H), 2.57 (s, 3H), 1.47-1.42 (m, 3H), 1.40 (d, J=7.2Hz, 3H)；ES-LCMS m/z 598.1(M+H).
Step 5：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- hydroxyethyls) -3- (trifluoromethyl) phenyl) urea
To 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- In (4- (1- hydroxyethyls) -3- (trifluoromethyl) phenyl) solution of urea (80mg, 0.134mmol) in MeOH (20mL) in batches Add 10%Pd/C (14.25mg, 0.134mmol).At room temperature, in H2The mixture is stirred under atmosphere 1 hour.At LCMS points After analysis shows that initial substance disappears.Reactant mixture is filtered, and is evaporated filtrate.Then, by prepare HPLC (instrument: The posts of Gilson 215/: Gemini C18 10u 150*25mm/ mobile phase As: water (0.01mol/L (NH4)HCO3)/Mobile phase B: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：28-58 (B%)) purifying residue, obtain pure products 1- (2- (5- ethoxies Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- hydroxyethyls) -3- (trifluoromethyl) Phenyl) urea (8.61mg, 0.018mmol, yield 13.35%)：1H NMR(400MHz,CD3OD)δ9.05(s,1H),8.08(d,J =2.0Hz, 1H), 7.88 (br.s., 2H), 7.77 (d, J=8.6Hz, 1H), 7.67 (d, J=8.6Hz, 1H), 5.18 (d, J= 6.0Hz, 1H), 4.18-4.13 (m, 2H), 2.56 (s, 3H), 1.49 (t, J=7.0Hz, 3H), 1.42 (d, J=6.6Hz, 3H)； ES-LCMS m/z 478.1(M+H)。
Embodiment 11：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) urea
Step 1：The fluoro- 1- isocyanatos benzene of the bromo- 2- of 4-
Triphosgene is added into mixture of the bromo- 2- fluoroanilines (720mg, 3.79mmol) of 4- in THF (30mL) (450mg,1.516mmol).At 50 DEG C, the mixture is stirred 1 hour.The mixture is concentrated, light yellow oil is obtained The fluoro- 1- isocyanatos benzene of the bromo- 2- of 4- (750mg, 3.47mmol, yield 92%)；ES-LCMS m/z 249.9(M+MeOH+H).
Step 2：1- (the bromo- 2- fluorophenyls of 4-) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) Urea
5- is added into mixture of the fluoro- 1- isocyanatos benzene (751mg, 3.48mmol) of the bromo- 2- of 4- in THF (50mL) (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine (450mg, 2.318mmol) and Et3N(0.645mL, 4.64mmol).Then, at 50 DEG C, the mixture is stirred 4 hours.Concentrate the mixture.In silica gel column chromatography (PE/EA=5: 1) residue is purified on.TLC (PE/EA=2 will be passed through：1,Rf=0.6) find that all fractions comprising product merge, and it is dense Contracting, obtain light yellow solid 1- (the bromo- 2- fluorophenyls of 4-) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole - 3- yls) urea (220mg, 0.536mmol, yield 23.14%)：1H NMR(400MHz,MeOD)δ:8.07 (t, J=4.8Hz, 1H), 7.38 (dd, J=2.4,10.8Hz, 1H), 7.32-7.29 (m, 1H), 6.76 (s, 1H), 1.58 (s, 6H)；ES-LCMS m/z 412.0,410.0(M+H)。
Step 3：1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
In N2Under atmosphere, to 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls -1,3,2- Dioxaborolan alkane -2- bases) pyridine (250mg, 0.649mmol), 1- (the bromo- 2- fluorophenyls of 4-) -3- (5- (1,1,1- tri- Fluoro- 2- methylpropanes -2- base) isoxazole -3-bases) urea (220mg, 0.536mmol) is in water (1mL) and 1,4- dioxanes (3mL) In mixture in add Cs2CO3(423mg, 1.298mmol) and PdCl2(dppf)-DCM adducts (53.0mg, 0.065mmol).Then, the mixture is stirred, and in micro-wave oven, is irradiated 30 minutes at 130 DEG C.The mixture is concentrated, is used in combination EA is extracted.The organic matter of merging is concentrated.By preparing TLC (PE/EA=2：1, Rf=residue 0.5) is purified, obtain yellowish-white Color solid 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (5- (1,1, The fluoro- 2- methylpropanes -2- bases of 1- tri-) isoxazole -3-base) urea (150mg, 0.161mmol, yield 24.74%)：1H NMR (400MHz,MeOD)δ:8.22 (t, J=4.8Hz, 1H), 7.95 (d, J=2.4Hz, 1H), 7.48-7.37 (m, 5H), 6.95- 6.81(m,3H),5.38-5.35(m,2H),4.20-4.14(m,2H),3.81(s,3H),1.62-1.37(m,9H)；ES-LCMS m/z 589.0(M+H)。
Step 4：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (5- (1,1,1- Three fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) urea
At 25 DEG C, 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorobenzene is stirred Base) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) ureas (150mg, 0.255mmol) and TFA ( 10%, 100mL in DCM) mixture 2 hours.The mixture is concentrated, and by preparing HPLC (MeCN/H2O as eluent, Acid condition) purifying residue, obtain white-yellowish solid 1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) - 2- fluorophenyls) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea (84.37mg, 0.177mmol, Yield 87%)：1H NMR(400MHz,MeOD)δ:8.17 (t, J=8.4Hz, 1H), 7.40 (dd, J=2.0,12.4Hz, 1H), 7.36-7.33 (m, 1H), 7.27 (d, J=2.4Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 6.77 (s, 1H), 4.12 (q, J= 7.2Hz, 2H), 1.59 (s, 6H), 1.46 (t, J=7.2Hz, 3H)；ES-LCMS m/z469.1(M+H).
Embodiment 12：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea
Step1：1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) 3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (200mg, 0.506mmol) in 1,4- dioxanes (30mL)3N (0.106mL, 0.759mmol), and Stirred 15 minutes at 25 DEG C.Then, DPPA (209mg, 0.759mmol) is added into the mixture, and is stirred 15 minutes.To In the mixture add 4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) aniline (124mg, 0.506mmol), and at 80 DEG C stir 3 hours.The mixture is concentrated, and by preparing TLC (DCM/MeOH=15:1,Rf= 0.45) residue is purified, 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- of light yellow solid are obtained Base) -4- methylpyrimidine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea (80mg, 0.107mmol, yield 21.08%)：1H NMR(400MHz,CD3OD)δ9.16(s,1H),8.08(s,1H),7.90 (s,1H),7.81-7.75(m,1H),7.64-7.62(m,1H),7.55(s,1H),7.26-7.20(m,2H),6.88-6.86 (m,2H),5.99-5.96(m,2H),4.71-4.64(m,2H),4.33-4.25(m,2H),4.12-4.05(m,2H),3.76 (s,3H),2.56(s,2H),2.50-2.30(m,3H),1.37-1.35(m,3H),1.18(s,3H)；ES-LCMS(m/z): 638.2(M+H)。
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by stirring 1- Pyridine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea (80mg, 0.125mmol) and TFA (10%in DCM, 30mL) mixture 2 hours.Concentrate the mixture.By preparing HPLC (instrument: Gilson GX 281；Post：Gemini 150*25mm*5um；Mobile phase A: water (0.05% ammonia spirit)；Mobile phase B ∶MeCN；Gradient: 36-66 (B%)；Flow velocity：25mL/min；Run time: 10min) purifying residue, obtain white solid 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methyl oxa- rings Butane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea (4.58mg, 8.85 μm of ol, yield 7.05%)：1H NMR (400MHz,CD3OD) δ 9.15 (s, 1H), 7.90 (d, J=2.4Hz, 1H), 7.77 (s, 1H), 7.63 (d, J=8.4Hz, 1H), 7.23 (d, J=8.4Hz, 1H), 5.99 (s, 1H), 4.68 (d, J=6.0Hz, 2H), 4.30 (d, J=5.6Hz, 2H), 4.11 (q, J=6.8Hz, 2H), 3.03 (s, 2H), 2.55 (s, 3H), 1.44-1.29 (m, 6H)；ES-LCMS m/z:518.1(M+H).
Embodiment 13:1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea
Step1：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (180mg, 0.455mmol) in 1,4- dioxanes (30mL)3N (0.095mL, 0.683mmol), and Stirred 15 minutes at 25 DEG C.Then, DPPA (188mg, 0.683mmol) is added into the mixture, and is stirred 15 minutes.To In the mixture add 4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) aniline (112mg, 0.455mmol), and at 80 DEG C stir 3 hours.The mixture is concentrated, and by preparing TLC (DCM/MeOH=20:1,Rf= 0.5) residue is purified, 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- of light yellow solid are obtained Base) -4- methylpyrimidine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea (100mg, 0.133mmol, yield 29.3%)：1H NMR(400MHz,CD3OD)δ9.10(s,1H),8.66(s,1H),8.07- 8.06 (m, 1H), 7.90 (s, 1H), 7.61 (d, J=8.4Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 7.22 (d, J= 8.4Hz, 1H), 6.91 (d, J=8.4Hz, 2H), 5.38 (s, 2H), 4.68 (d, J=5.6Hz, 2H), 4.30 (d, J=5.6Hz, 2H), 4.19-4.12 (m, 2H), 3.81-3.74 (m, 3H), 3.02 (s, 2H), 2.59-2.52 (m, 3H), 1.43 (t, J= 7.2Hz,3H),1.35(s,3H)；ES-LCMS(m/z):638.1(M+H).
Step 2：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by stirring 1- Pyridine -5- bases) -3- (4- ((3- methy oxetane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea (100mg, 0.157mmol) and TFA (10%, the 30mL in DCM) mixture 2 hours.Concentrate the mixture.By preparing HPLC (instruments ∶Gilson GX 281；Post: Gemini 150*25mm*5um；Mobile phase A: water (0.05% ammonia spirit)；Mobile phase B: MeCN；Gradient: 40-70 (B%)；Flow velocity：25mL/min；Run time: 10min) purifying residue, obtain the 1- of white solid (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea (49mg, 0.092mmol, yield 58.8%)：1H NMR(400MHz, CD3OD) δ 9.03 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=2.0Hz, 1H), 7.63-7.61 (m, 1H), 7.24-7.22 (m, 1H), 4.69 (d, J=6.0Hz, 2H), 4.30 (d, J=6.0Hz, 2H), 4.14 (q, J=6.8Hz, 2H), 3.03 (s, 2H), 2.55 (s, 3H), 1.48 (t, J=7.2Hz, 3H), 1.35 (s, 6H)；ES-LCMS m/z:518.1(M+H).
Embodiment 14：1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionic acid
By 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) ethyl propionate (2g, 6.26mmol) in MeOH Mixture in (30mL) is added in solution of the LiOH (0.450g, 18.79mmol) in water (30mL).Then, at 60 DEG C Under, stir the mixture 10 hours.The mixture is acidified to pH=6.0 with 6.0mol/L HCl, DCM/MeOH is then used (10/1,50mL × 3) extract.By the organic layer of merging through Na2SO4Dry, and concentrate, obtain 2, the 2- dimethyl of white solid- 3- (4- nitros -2- (trifluoromethyl) phenyl) propionic acid (1.5g, 4.48mmol, yield 71.5%)：1H NMR(400MHz,CD3OD) δ:8.48 (d, J=2.4Hz, 1H), 8.37 (dd, J=2.4,8.8Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 3.24 (s, 2H),1.17(s,6H)。
Step 2：2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionamide
To be cooled to 0 DEG C 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionic acid (8.5g, Oxalyl dichloro (3.07mL, 35.0mmol) 29.2mmol) and in mixtures of the DMF (0.2mL) in DCM (250mL) is added, and At 25 DEG C, the mixture is stirred 1 hour.Concentrate the mixture, and the addition DCM (250mL) into residue.At 25 DEG C, In NH3Under, stir the mixture 2 hours.Concentrate the mixture.By residue distribution in EA (200mL) and H2O (200mL) it Between.By organic layer salt water washing, through Na2SO4It is dried, filtered and concentrated, obtains 2, the 2- dimethyl -3- (4- of yellow oil Nitro -2- (trifluoromethyl) phenyl) propionamide (5.5g, 10.74mmol, yield 36.8%)：1H NMR(400MHz,CD3OD)δ: 8.49 (d, J=2.0Hz, 1H), 8.37 (dd, J=2.4,8.8Hz, 1H), 7.73 (d, J=8.8Hz, 1H), 3.22 (s, 2H), 1.18(s,6H)；ES-LCMS(m/z):291.0(M+H).
Step 3：2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile (propanenitrile)
To 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionamides (5g, 17.23mmol) and Et3N (3.65mL, 25.8mmol) is added in the mixture of (7.20mL, 51.7mmol) in DCM (50mL).At 25 DEG C, stirring should Mixture 10 hours.With the NaHCO of saturation3The mixture is washed with salt solution (50mL × 2).Through MgSO4Dry organic layer and dense Contracting.In silica gel column chromatography (PE/EA=10:1) residue is purified on.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find bag All fractions containing product merge, and concentrate, and obtain 2, the 2- dimethyl -3- (4- nitros -2- (trifluoromethyl) of light yellow solid Phenyl) propionitrile (4g, 13.55mmol, yield 79%)：1H NMR(400MHz,CD3OD)δ:8.56 (d, J=2.4Hz, 1H), 8.50 (dd, J=2.0,8.4Hz, 1H), 8.05 (d, J=8.4Hz, 1H), 3.21 (s, 2H), 1.43 (s, 6H)；ES-LCMS(m/ z):290.0(M+H2O)。
Step 4：3- (4- amino -2- (trifluoromethyl) phenyl) -2,2- dimethyl propionitrile
To 2,2- dimethyl -3- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile (4g, 14.69mmol) at EA (100mL) In mixture in add SnCl2·H2O (12.20g, 58.8mmol), and flow back 2 hours.After cooling, the mixing is used The NaHCO of saturation3Solution is neutralized to pH=7.5.The mixture is extracted with EA (100mL × 4).The organic extract of merging is used Salt water washing, through MgSO4It is dried, filtered and concentrated.In silica gel column chromatography (PE/EA=5:1) residue is purified on.It will pass through TLC (PE/EA=2：1, Rf=0.45) find that all fractions comprising product merge, and concentrate, obtain the 3- of light yellow solid (4- amino -2- (trifluoromethyl) phenyl) -2,2- dimethyl propionitrile (3.5g, 13.29mmol, yield 90%)：1H NMR (400MHz,CD3OD)δ:7.40 (d, J=8.4Hz, 1H), 6.98 (d, J=2.4Hz, 1H), 6.86 (dd, J=2.4,8.4Hz, 1H),2.90(s,2H),1.34(s,6H)；ES-LCMS m/z:243.1(M+H).
Step 5：1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (200mg, 0.503mmol) in 1,4- dioxanes (30mL)3N (0.105mL, 0.755mmol), and Stirred 15 minutes at 25 DEG C.Then, DPPA (208mg, 0.755mmol) is added into the mixture, and is stirred 15 minutes.To 3- (4- amino -2- (trifluoromethyl) phenyl) -2,2- dimethyl propionitrile (122mg, 0.503mmol) is added in the mixture, and Stirred 3 hours at 80 DEG C.The mixture is concentrated, and by preparing TLC (DCM/MeOH=20:1,Rf=0.5) purify remnants Thing, obtain light yellow solid 1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- ((4- methoxy-benzyls) epoxide) -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea (80mg, 0.113mmol, Yield 22.5%)：1H NMR(400MHz,CD3OD)δ:9.04(s,1H),8.08-8.04(m,1H),7.96(s,1H),7.85 (s, 1H), 7.80-7.75 (m, 1H), 7.67-7.65 (m, 1H), 7.25 (d, J=8.4Hz, 2H), 6.91-6.84 (m, 2H), 4.59(s,2H),4.16-4.11(m,2H),3.77(s,3H),3.03(s,2H),2.55(s,3H),1.50-1.45(m,3H), 1.38(s,6H)；ES-LCMS(m/z):515.1(M-PMB+H).
Step 6：1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
At 25 DEG C, 1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethoxies are stirred Base -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (80mg, 0.126mmol) and TFA Mixture in (10%, the 30mL in DCM) 2 hours.Concentrate the mixture.By preparing HPLC (instrument: Gilson GX281；Post: Gemini 150*25mm*5um；Mobile phase A: water (0.05% ammonia spirit)；Mobile phase B: MeCN；Gradient: 42- 72 (B%)；Flow velocity：25mL/min；Run time: 10min) purifying residue, obtain the 1- (4- (2- cyano group -2- of white solid Methyl-propyl) -3- (trifluoromethyl) phenyl) (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl is phonetic by -3- Pyridine -5- bases) urea (22.67mg, 0.043mmol, yield 34.3%)：1H NMR(400MHz,CD3OD)δ:9.03(s,1H),8.06 (s, 1H), 7.96 (s, 1H), 7.86-7.85 (m, 1H), 7.68-7.66 (m, 2H), 4.14 (q, J=7.2Hz, 2H), 3.03 (s, 2H), 2.55 (s, 3H), 1.48 (t, J=7.2Hz, 3H), 1.38 (s, 6H)；ES-LCMS m/z:515.1(M+H).
Embodiment 15：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
Step 1：The chloro- 4- methylpyrimidines -5- amine of 2-
To at 20 DEG C, in N2The chloro- 6- methyl-5-nitros pyrimidines (10g, 48.1mmol) of 2,4- bis- of lower stirring and NH4Cl It is disposable in the solution of (25.7g, 481mmol) in MeOH (100mL) to add zinc (31.4g, 481mmol).At 70 DEG C, stir Mix reactant mixture 50 hours.The mixture is filtered, and concentrates filtrate in a vacuum.Pass through silica gel column chromatography (DCM/MeOH= 30:1) residue is purified.TLC (EA/EA=1=1 will be passed through：1,Rf=0.6) find that all fractions comprising product merge, and Concentration, obtains the chloro- 4- methylpyrimidines -5- amine of 2- (2g, 13.93mmol, yield 29.0%) of light yellow solid：1H NMR (400MHz,CDCl3)δ:7.95(s,1H),3.66(s,2H),2.88(s,3H)；ES-LCMS m/z:144.2(M+H).
Step 2：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- amine
To at 20 DEG C, in N23- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- of lower stirring Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (3.22g, 8.36mmol), the chloro- 4- methylpyrimidines -5- amine of 2- (1g, 6.97mmol) and Cs2CO3Disposably added in the solution of (5.67g, 17.41mmol) in DMF (3mL) and water (1mL) PdCl2(PPh3)2(0.244g,0.348mmol).At 110 DEG C, heating response container 3 hours.Then, solution is concentrated, and Distribution is between EA and water.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel Column chromatography TLC (PE/EA=1：1) residue is purified.TLC (PE/EA=1 will be passed through：1, Rf=0.3) find to include the institute of product There is fraction merging, and concentrate, obtain 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- of light yellow solid Base) -4- methylpyrimidine -5- amine (1.6g, 4.37mmol, yield 62.7%)：1H NMR(400MHz,CDCl3)δ:8.68(s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.46 (d, J=8.4Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 5.48 (s, 2H), 4.20 (q, J=7.2Hz, 2H), 3.80 (s, 3H), 3.64 (s, 2H), 2.45 (s, 3H), 1.47 (t, J=7.2Hz, 3H)；ES- LCMS m/z:367.1(M+H)。
Step 3：3- isocyanatos -5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole
At 50 DEG C, stirring 5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3- amine (300mg, 1.545mmol) and mixture of the triphosgene (183mg, 0.618mmol) in THF (30mL) 0.5 hour.The mixture is concentrated, Obtain yellow solid 3- isocyanatos -5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole (300mg, 1.186mmol, yield 77%)：ES-LCMS m/z:253.0(M+MeOH).
Step 4：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
Exist to 3- isocyanatos -5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole (100mg, 0.454mmol) 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is added in mixture in THF (50mL) Pyrimidine -5- amine (100mg, 0.273mmol) and Et3N(0.126mL,0.908mmol).Then, at 50 DEG C, the mixing is stirred Thing 1 hour.Other 3- isocyanatos -5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole is added into the mixture The solution of (100mg, 0.454mmol) in THF (15mL), and at 50 DEG C, stir the mixture 4 hours.Concentrate the mixing Thing.By preparing TLC (DCM/MeOH=10:1, Rf=residue 0.6) is purified, obtain 1- (2- (the 5- ethoxies of yellow solid Base -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methyl of 1,1,1- tri- Propane -2- base) isoxazole -3-bases) urea (60mg, 0.102mmol).At 25 DEG C, 1- (2- (5- ethyoxyls -6- ((4- first is stirred Oxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) is different by -3- Oxazole -3- bases) mixture of the urea (60mg, 0.102mmol) in TFA (10%, the 30mL in DCM) 1 hour.Concentrate the mixing Thing, and by preparing HPLC (MeCN/H2O is used as eluent, alkalescence condition) purifying residue, obtain the 1- (2- of white solid (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methyl of 1,1,1- tri- Propane -2- base) isoxazole -3-bases) urea (5.97mg, 0.013mmol, yield 2.82%)：1H NMR(400MHz,CD3OD+ CDCl3)δ:9.09 (s, 1H), 8.05 (d, J=2.0Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 6.70 (s, 1H), 4.14 (q, J=7.2Hz, 2H), 2.55 (s, 3H), 1.58 (s, 6H), 1.48 (t, J=6.8Hz, 3H)；ES-LCMS m/z 467.1(M+ H)。
Embodiment 16：1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
Step 1：The bromo- 2- isocyanatos -3- methylpyrazines of 5-
Three are added into mixture of the bromo- 3- methylpyrazines -2- amine (450mg, 2.393mmol) of 5- in THF (30mL) Phosgene (284mg, 0.957mmol).At 50 DEG C, the mixture is stirred 1 hour.The mixture is concentrated, pale yellowish oil is obtained The bromo- 2- isocyanatos -3- methylpyrazines of 5- (500mg, 0.963mmol, yield 40.2%) of thing：ES-LCMS m/z 247.9 (M+MeOH+H)。
Step 2：1- (the bromo- 3- methylpyrazines -2- bases of 5-) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) different Evil Azoles -3- bases) urea
Into mixture of the bromo- 2- isocyanatos -3- methylpyrazines (507mg, 2.369mmol) of 5- in THF (50mL) Add 5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine (400mg, 2.060mmol) and Et3N(0.573mL, 4.12mmol).At 50 DEG C, the mixture is stirred 4 hours.Concentrate the mixture.In silane column chromatography (PE/EA=5:1) on Purify residue.TLC (PE/EA=2 will be passed through：1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain To 1- (the bromo- 3- methylpyrazines -2- bases of 5-) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) different Evil of light yellow solid Azoles -3- bases) urea (150mg, 0.187mmol, yield 9.10%)：1H NMR(400MHz,CD3OD)δ:7.79(s,1H),6.92 (s,1H),2.58(s,3H),1.52(s,6H)；ES-LCMS m/z 409.9(M+2).
Step 3：1- (5- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- methylpyrazines -2- Base) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
In N2Under atmosphere, to 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls -1,3,2- Dioxaborolan alkane -2- bases) pyridine (80mg, 0.208mmol), 1- (the bromo- 3- methylpyrazines -2- bases of 5-) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) urea (85mg, 0.208mmol) is in water (1ml) and 1,4- dioxanes Add Cs in mixture in (3ml)2CO3(135mg, 0.415mmol) and PdCl2(dppf)(15.19mg,0.021mmol).So Afterwards, the mixture is stirred, and in irradiation 30 minutes at 120 DEG C in micro-wave oven.The mixture is concentrated, and is extracted with EA.Concentration The organic matter of merging.By preparing TLC (PE/EA=2：1, Rf=residue 0.5) is purified, obtain the 1- (5- (5- of yellow solid Ethyoxyl -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- methylpyrazine -2- bases) -3- (5- (the fluoro- 2- of 1,1,1- tri- Methylpropane -2- base) isoxazole -3-bases) urea (20mg, 0.014mmol, yield 6.57%)：1H NMR(400MHz,CD3OD)δ: 8.71 (d, J=6.4Hz, 1H), 8.38 (s, 1H), 7.89 (d, J=12.0Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 5.42 (d, J=3.6Hz, 2H), 4.62 (s, 2H), 4.23-4.17 (m, 2H), 3.82 (s, 3H), 1.72-1.51 (m, 6H), 1.47 (t, J=6.8Hz, 3H)；ES-LCMS m/z 587.1(M+H).
Step 4：1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
At 25 DEG C, 1- (5- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- methyl pyrroles are stirred Piperazine -2- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) ureas (20mg, 0.034mmol) and HCl 4mol/L, 20mL in (dioxanes) mixture 2 hours.Concentrate the mixture.By preparing HPLC (MeCN/H2O is as washing De- liquid, acid condition) purifying residue, obtain 1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- of white solid Base) -3- methylpyrazine -2- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea hydrochloride (1.2mg, 2.386 μm of ol, yield 7.00%)：1H NMR(400MHz,DMSO-d6)δ:11.92(s,1H),11.13(s,1H), 9.28 (s, 1H), 8.73 (s, 1H), 7.72 (s, 1H), 7.43 (d, J=2.0Hz, 1H), 6.89 (s, 1H), 4.02 (q, J= 7.1Hz, 2H), 2.51 (s, 3H), 1.53 (s, 6H), 1.33 (t, J=6.9Hz, 3H)；ES-LCMS m/z 467.2(M+H).
Embodiment 17：1- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- (piperazine -1- ylmethyls) -3- (trifluoromethyl) phenyl) urea
Step 1：(4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) t-butyl carbamate
In N2Under atmosphere, to 5- bromopyridine -2- alcohol (600mg, 3.45mmol), (4- ((t-butoxy carbonyl) amino) benzene Base) Cs is added in mixture of the boric acid (817mg, 3.45mmol) in water (3mL) and 1,4- dioxanes (9mL)2CO3 (2247mg,6.90mmol)、PdCl2(dppf)(126mg,0.172mmol).Then, the mixture is stirred, and in micro-wave oven In irradiation 1 hour at 100 DEG C.The mixture is concentrated, is extracted with EA.Concentrate organic phase.By prepare TLC (DCM/MeOH=10: 1) purify residue, obtain (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) t-butyl carbamate (100mg, 0.349mmol, yield 10.13%)：1H NMR(400MHz,CDCl3)δ:7.67 (dd, J=2.4,9.6Hz, 1H), 7.43- 7.40 (m, 1H), 7.35 (d, J=8.8Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 6.60 (d, J=9.6Hz, 1H), 1.40 (s,9H)；ES-LCMS m/z 287.2(M+H).
Step 2：5- (4- aminophenyls) pyridine -2 (1H) -one
Exist to (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) t-butyl carbamate (100mg, 0.349mmol) TFA (39.8mg, 0.349mmol) is added in solution in DCM (10mL), is then stirred 2 hours at 25 DEG C.Concentrate the mixing Thing, obtains 5- (4- aminophenyls) pyridine -2 (1H) -one (60mg, 0.322mmol, yield 92%：ES-LCMS m/z 187.1 (M+H)。
Step 3：4- isocyanatos -2- (trifluoromethyl) benzaldehyde
Add into mixture of 4- amino -2- (trifluoromethyl) benzaldehyde (90mg, 0.476mmol) in THF (30mL) Enter double trichloromethyl esters (56.5mg, 0.190mmol).Then, at 50 DEG C, the mixture is stirred 0.5 hour.Concentrate the mixing Thing, obtains 4- isocyanatos -2- (trifluoromethyl) benzaldehyde (100mg, 0.465mmol, yield 98%).
Step 4：1- (4- formoxyls -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) benzene Base) urea
Into mixture of 5- (4- aminophenyls) pyridine -2 (1H) -one (60mg, 0.322mmol) in THF (15mL) Add 4- isocyanatos -2- (trifluoromethyl) benzaldehyde (90mg, 0.419mmol), Et3N(65.2mg,0.644mmol).So Afterwards, the mixture is stirred at 50 DEG C 4 hours.The mixture is concentrated, and by preparing TLC (DCM:MeOH=10: 1) purify residual Excess, obtains 1- (4- formoxyls -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) urea (20mg, 0.050mmol, yield 15.47%)：1H NMR(400MHz,CD3OD) δ 10.20 (t, J=2.0Hz, 1H), 8.17 (d, J=2.0Hz, 1H), 8.10 (d, J=8.4Hz, 1H), 7.95 (dd, J=2.8,9.6Hz, 1H), 7.81 (dd, J=2.4, 8.8Hz, 1H), 7.70 (d, J=2.8Hz, 1H), 7.58 (dd, J=2.0,6.8Hz, 2H), 7.53 (dd, J=2.0,8.4Hz, 2H), 6.63 (d, J=7.2Hz, 1H)；ES-LCMS m/z 402.1(M+H).
Step 5：4- (4- (3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) urea groups) -2- (trifluoromethyl) benzyls Base) piperazine -1- carboxylic acid tert-butyl esters
At 25 DEG C, stirring 1- (4- formoxyls -3- (trifluoromethyl) phenyl) -3- (4- (6- oxos -1,6- dihydropyridine - 3- yls) phenyl) urea (35mg, 0.087mmol), piperazine -1- carboxylic acid tert-butyl esters (0.031mL, 0.174mmol), piperazine -1- carboxylic acids Mixture of the tert-butyl ester (0.031mL, 0.174mmol) in DCM (10mL) 2 hours.Then, it is added portionwise into the mixture NaBH (OAc) 3 (18.48mg, 0.087mmol), then, at 25 DEG C, is stirred 12 hours.The mixture is concentrated, and passes through system Standby TLC purifies residue, obtains 4- (4- (3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) urea groups) -2- (fluoroforms Base) benzyl) piperazine -1- carboxylic acid tert-butyl esters (20mg, 0.035mmol, yield 40.1%)：ES-LCMS m/z 572.2(M+H).
Step 6：1- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- (piperazine -1- ylmethyls) -3- (three Methyl fluoride) phenyl) urea
At 25 DEG C, 4- (4- (3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) urea groups) -2- (trifluoros are stirred Methyl) benzyl) piperazine -1- carboxylic acid tert-butyl esters (20mg, 0.035mmol) and HCl/MeOH (4mol/L, 10mL, 40.0mmol) Mixture 2 hours.The mixture is concentrated, by preparing HPLC purifying, 1- (4- (6- oxo -1,6- dihydropyridine -3- bases) are obtained Phenyl) -3- (4- (piperazine -1- ylmethyls) -3- (trifluoromethyl) phenyl) urea dihydrochloride (2.48mg, 4.56 μm of ol, yield 13.02%)：1H NMR(400MHz,CD3OD)δ:8.27 (d, J=8.0Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.92 (d, J=8.0Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 7.60-7.59 (m, 4H), 6.96 (d, J=9.2Hz, 1H), 4.35 (s,2H),3.56(s,4H),3.39(s,4H)；ES-LCMS m/z 472.2(M+H).
Embodiment 18:：1- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step1：1- (4- (6- (benzyloxy) -4- ethoxy pyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 2- (benzyloxy) -4- ethyoxyl -5- iodine pyridines (150mg, 0.422mmol) in 1,4- dioxanes (3mL) and water 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) benzene is added in mixture in (1mL) Base) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (237mg, 0.465mmol), Cs2CO3(275mg, 0.845mmol) and PdCl2(dppf)(30.9mg,0.042mmol).Under microwave, in N2 at 110 DEG C The mixture is stirred under atmosphere 30 minutes.Then, reaction residue is filtered, filtrate is concentrated, and pass through TLC (PE/EA=1：1, Rf =0.6) purify, obtain 1- (4- (6- (benzyloxy) -4- ethoxy pyridine -3- bases) -2- fluorophenyls) -3- (4- of yellow solid ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (100mg, 0.147mmol, yield 34.8%)：1H NMR(400MHz,CD3OD) δ 8.08 (t, J=8.4Hz, 1H), 7.94 (s, 1H), 7.78 (d, J=2.4Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.45-7.43 (m, 2H), 7.37-7.35 (m, 1H), 7.32-7.29 (m, 3H), 7.26- 7.23 (m, 1H), 6.62 (d, J=8.4Hz, 1H), 6.47 (s, 1H), 5.35 (s, 2H), 4.89 (d, J=6.4Hz, 2H), 4.62 (d, J=7.2Hz, 2H), 4.16-4.10 (m, 2H), 1.72 (s, 3H), 1.38 (t, J=6.8Hz, 3H)；ES-LCMS m/z 612.2(M+H)。
Step 2：1- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 1- (4- (6- (benzyloxy) -4- ethoxy pyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) in mixture of the urea (100mg, 0.164mmol) in MeOH (10mL) plus Enter Pd/C (20mg, 10%).In H2Under atmosphere, at 25 DEG C, the mixture is stirred 16 hours.Reaction residue is filtered and dense Contracting.By preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying residue, obtain the 1- (4- (4- of white solid Ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) oxygen Base) -3- (trifluoromethyl) phenyl) urea (40.13mg, 0.077mmol, yield 47.1%)：1H NMR(400MHz,CD3OD)δ 8.11 (t, J=8.8Hz, 1H), 7.80 (d, J=2.8Hz, 1H), 7.57 (dd, J=2.8Hz, 8.4Hz, 1H), 7.38 (s, 1H), 7.30 (dd, J=2.4,8.4Hz, 1H), 7.21 (d, J=8.8Hz, 1H), 6.65 (d, J=8.8Hz, 1H), 6.01 (s, 1H), 4.92 (d, J=6.8Hz, 2H), 4.65 (d, J=6.8Hz, 2H), 4.16-4.11 (m, 2H), 1.75 (s, 3H), 1.41 (t, J=7.2Hz, 2H)；ES-LCMS m/z 522.2(M+H).
Embodiment 19：1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：(E) -3- (furans -2- bases) acrylic acid
At room temperature, to furans -2- formaldehyde (30g, 312mmol) and malonic acid (35.7g, 343mmol) in pyridine Piperidines (3.09mL, 31.2mmol) is added in mixture in (300mL), and at 100 DEG C, stirs the mixture 16 hours. Reaction solution is poured into water (200mL), and is acidified with 6M hydrochloric acid.Obtained sediment is collected by filtration, obtain (E)- 3- (furans -2- bases) acrylic acid (32g, 227mmol, yield 72.7%)：1H NMR(400MHz,CD3OD) δ 7.61 (d, J= 1.6Hz, 1H), 7.42 (d, J=15.6Hz, 1H), 6.73 (d, J=3.2Hz, 1H), 6.53 (dd, J=2.0,3.6Hz, 1H), 6.22 (d, J=15.6Hz, 1H)；ES-LCMS m/z 139.1(M+H).
Step 2：(E) -3- (furans -2- bases) acryloyl group azide
Under ice-cooling, to (E) -3- (furans -2- bases) acrylic acid (25g, 181mmol) and Et3N(30.3mL, DPPA (54.8g, 199mmol) 217mmol) is added in the mixture in THF (50mL).At 25 DEG C, the mixture 4 is stirred Hour.Reaction solution is poured into EA (300mL) and the NaHCO of saturation3In the mixture of the aqueous solution (300mL), and use EA (200mL) extracts the mixture.Through anhydrous Na2SO4Dry extract, and evaporation solvent under reduced pressure.Remnants are washed with MeOH Thing, obtains (E) -3- (furans -2- bases) acryloyl group azide (24g, 144mmol, yield 80%)：1H NMR(400MHz, CDCl3) δ 7.53-7.50 (m, 1H), 7.47 (s, 1H), 6.71 (d, J=3.2Hz, 1H), 6.50 (dd, J=2.0,3.6Hz, 1H), 6.30 (d, J=3.6Hz, 1H).
Step 3：Furans simultaneously [3,2-c] pyridine -4 (5H) -one
At 100 DEG C, stirring (E) -3- (furans -2- bases) acryloyl group azide (10g, 61.3mmol) is in toluene Mixture in (100mL) 30 minutes.Evaporation solvent.Residue is dissolved in 1,2- dichloro-benzenes (90g, 613mmol) and iodine In (0.062g, 0.245mmol).At 180 DEG C, the mixture is stirred 2 hours.Evaporation solvent.Residue is dissolved in MeOH In (200mL).Sediment is filtered out, filtrate is concentrated, and is washed with TBME (50mL), furans simultaneously [3,2-c] pyridine -4 is obtained (5H) -one (5g, 31.5mmol, yield 51.3%)：1H NMR(400MHz,CD3OD) δ 7.71 (d, J=2.0Hz, 1H), 7.32 (d, J=7.2Hz, 1H), 6.95 (dd, J=1.2,2.4Hz, 1H), 6.75 (dd, J=0.8,7.2Hz, 1H)；ES-LCMS m/z 136.1(M+H)。
Step 4：7- bromines furans simultaneously [3,2-c] pyridine -4 (5H) -one
At 0 DEG C, through 10 minutes, to furans simultaneously [3,2-c] pyridine -4 (5H) -one (5g, 37.0mmol) in MeCN Solution of the NBS (8.56g, 48.1mmol) in MeCN is added in mixture in (50mL).At 0 DEG C, it is outstanding that stirring is obtained Supernatant liquid 1 hour, and it is warming up to room temperature 10 minutes.Water (250mL) and the NaHCO of saturation are added into the mixture3The aqueous solution (10mL).Be collected by filtration white-yellowish solid, and dry, obtain 7- bromines furans simultaneously [3,2-c] pyridine -4 (5H) -one (1.5g, 5.96mmol, yield 16.10%)：1H NMR(400MHz,CD3OD) δ 7.82 (d, J=2.0Hz, 1H), 7.51 (s, 1H), 7.05 (d, J=2.4Hz, 1H)；ES-LCMS m/z 214.0,215.9(M+H).
Step 5：1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 7- bromines furans simultaneously [3,2-c] pyridine -4 (5H) -one (250mg, 1.168mmol) in 1,4- dioxanes (12mL) and 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) are added in mixture in water (4mL) Phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (656mg, 1.285mmol)、PdCl2(dppf) (85mg, 0.117mmol) and Cs2CO3(761mg,2.336mmol).Under microwave, in N2 Under atmosphere, the mixture is stirred in 110 DEG C 30 minutes.By preparing HPLC (MeCN/H2O is used as eluent, acid condition) it is pure Change residue, obtain 1- (the fluoro- 4- of 2- (4- oxos -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) benzene of white solid Base) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (48.18mg, 0.089mmol, Yield 7.63%)：1H NMR(400MHz,CD3OD) δ 8.20 (t, J=8.4Hz, 1H), 7.85 (d, J=2.0Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.61-7.51 (m, 4H), 7.07 (d, J=2.0Hz, 1H), 6.62 (d, J=8.8Hz, 1H), 4.89 (d, J=6.8Hz, 2H), 4.63 (d, J=7.2Hz, 2H), 1.72 (s, 3H)；ES-LCMS m/z 518.0(M+H).
Embodiment 20：1- (4- (5- ring propoxyl group -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 5- rings propoxyl group pyridines of 3-
Bromine cyclopropane is added into mixture of the 5- bromopyridine -3- alcohol (5g, 28.7mmol) in DMF (50mL) (3.82g, 31.6mmol), NaI (0.431g, 2.87mmol) and K2CO3(7.94g,57.5mmol).At 150 DEG C, stirring should Mixture 32 hours.Reactant is filtered, concentrated, and pass through silica gel column chromatography (PE/EA=5:1) purify.TLC (PE/ will be passed through EA=5:1, Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain the bromo- 5- rings third of 3- of yellow oil Epoxide pyridine (1.5g, 5.61mmol, yield 19.51%)：1H NMR(400MHz,CDCl3)δ8.31-8.28(m,2H),7.52 (t, J=2.4Hz, 1H), 3.78-3.75 (m, 1H), 0.84-0.78 (m, 4H)；ES-LCMS m/z 214.0,216.0(M+H).
Step 2：The bromo- 5- rings propoxyl group pyridine 1- oxides of 3-
M-CPBA is added into mixture of the bromo- 5- rings propoxyl group pyridines (1.5g, 7.01mmol) of 3- in DCM (50mL) (1.814g,10.51mmol).At 25 DEG C, the mixture is stirred 16 hours.By mixture distribution is in DCM (50mL) and satisfies And Na2SO3 solution (50mL × 3) between.By the organic extract of merging salt water washing, through MgSO4Dry, filter and dense Contracting.Obtain bromo- the third oxygen of the 5 ring yl pyridines 1- oxides (1.2g, 3.91mmol, yield 55.8%) of 3-：1H NMR(400MHz, CDCl3)δ8.08-8.07(m,1H),8.04-8.03(m,1H),7.16-7.15(m,1H),3.82-3.79(m,1H),0.87- 0.81(m,4H)；ES-LCMS m/z 229.9,231.9(M+H).
Step 3：The chloro- 3- rings propoxyl group pyridines of the bromo- 2- of 5-
Add into mixture of the bromo- 5- rings propoxyl group pyridine 1- oxides (1.2g, 5.22mmol) of 3- in DCM (20mL) Enter POCl3(9.72mL,104mmol).At 45 DEG C, the mixture is stirred 16 hours.By reactant distribution at DCM (100mL) With the NaHCO of saturation3Between solution (150mL).By the organic extract of merging salt water washing, through Na2SO4Dry, filtering is simultaneously Concentration.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find bag All fractions containing product merge, and concentrate, obtain yellow oil the chloro- 3- rings propoxyl group pyridines of the bromo- 2- of 5- (1g, 3.42mmol, yield 65.6%)：1H NMR(400MHz,CDCl3) δ 8.08 (d, J=2.0Hz, 1H), 7.69 (d, J=2.0Hz, 1H),3.84-3.79(m,1H),0.91-0.89(m,4H)；ES-LCMS m/z 247.9,249.9(M+H).
Step 4：The bromo- 3- rings propoxyl group -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine
(4- is added into mixture of the chloro- 3- rings propoxyl group pyridines (1g, 4.02mmol) of the bromo- 2- of 5- in DMF (10mL) Methoxyphenyl) methanol (0.612g, 4.43mmol) and NaH (0.241g, 6.04mmol).At 120 DEG C, the mixture is stirred 16 hours.The mixture is evaporated, and is distributed between DCM (50mL × 2) and water (50mL).By the organic extract salt of merging Water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC will be passed through (PE/EA=5:1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain the bromo- 3- rings of 5- of yellow solid Propoxyl group -2- ((4- methoxy-benzyls) epoxide) pyridine (1.2g, 2.399mmol, yield 59.6%)：1H NMR(400MHz, CDCl3) δ 7.77 (d, J=2.0Hz, 1H), 7.48 (d, J=2.4Hz, 1H), 7.39-7.37 (m, 2H), 6.86 (dd, J= 2.4,6.8Hz,2H),5.34(s,2H),3.79(s,2H),3.72-3.68(m,1H),0.84-0.79(m,4H)；ES-LCMS m/z 350.0,352.0(M+H)。
Step 5：1- (4- (5- ring propoxyl group -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To the bromo- 3- rings propoxyl group -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (180mg, 0.514mmol) in 1,4- bis- 1- is added in mixture in oxane (12mL) and water (4mL), and ((4,4,5,5- tetramethyl -1,3,2- dioxa boron is miscellaneous by the fluoro- 4- of 2- Pentamethylene -2- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (289mg,0.565mmol)、Cs2CO3(335mg, 1.028mmol) and PdCl2(dppf)(37.6mg,0.051mmol).110 At DEG C, in N2Under atmosphere, the mixture is stirred 16 hours.Reactant is filtered, and evaporates filtrate.By preparing TLC (PE/EA= 3:1,Rf=residue 0.6) is purified, obtain 1- (4- (5- ring propoxyl group -6- ((4- methoxy-benzyls) oxygen of yellow oil Base) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) Urea (180mg, 0.275mmol, yield 53.6%)：1H NMR(400MHz,CDCl3) δ 8.14 (t, J=8.0Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.53 (dd, J=2.0,4.0Hz, 3H), 7.40 (d, J=8.8Hz, 2H), 7.14 (s, 1H), 7.07 (d, J=2.8Hz, 1H), 6.86 (dd, J=2.0,6.4Hz, 2H), 6.40-6.37 (m, 1H), 5.41 (s, 2H), 4.94 (d, J =6.4Hz, 2H), 4.56 (d, J=7.2Hz, 2H), 3.78 (s, 3H), 2.17 (s, 1H), 1.71 (s, 3H), 0.85-0.80 (m, 4H)；ES-LCMS m/z 534.0(M-PMB+H).
Step 6：1- (4- (5- ring propoxyl group -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 1- (4- (5- ring propoxyl group -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (180mg, 0.275mmol) is in MeOH Mixture in (10mL) adds Pd/C (18mg, 10%).At 25 DEG C, in H2The mixture is stirred under atmosphere 16 hours.Steam Reactant is sent out, and by preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying, obtain the 1- (4- of white solid (5- ring propoxyl group -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) Epoxide) -3- (trifluoromethyl) phenyl) urea (46.27mg, 0.085mmol, yield 30.9%)：1H NMR(400MHz,CD3OD)δ 8.14 (t, J=8.8Hz, 1H), 7.79 (d, J=2.8Hz, 1H), 7.54 (dd, J=2.4Hz, 9.2Hz, 2H), 7.39-7.32 (m, 2H), 7.28 (d, J=2.4Hz, 1H), 6.62 (d, J=9.2Hz, 1H), 4.90 (d, J=6.4Hz, 2H), 4.62 (d, J= 7.6Hz,2H),3.94-3.89(m,1H),1.72(s,3H),0.89-0.77(m,4H)；ES-LCMS m/z 534.2(M+H).
Embodiment 21：1- (4- (5- methoxyl group -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 5- methoxypyridines 1- oxides of 3-
M-CPBA is added into mixture of the bromo- 5- methoxypyridines (3.6g, 19.15mmol) of 3- in DCM (50mL) (3.96g,22.98mmol).At 25 DEG C, the mixture is stirred 16 hours.By reaction residue distribution in DCM (100mL) and The Na of saturation2SO3Between solution (100mL × 2).By the organic extract of merging salt water washing, through MgSO4Dry, filtering is simultaneously Concentration.Obtain the bromo- 5- methoxypyridines 1- oxides of 3- (4g, 14.70mmol, yield 77%)：1H NMR(400MHz,CDCl3) δ 8.02-8.01 (m 1H), 7.92-7.91 (m 1H), 7.03 (t, J=1.6Hz, 1H), 3.93 (s, 3H)；ES-LCMS m/z 204.1,206.1(M+H)。
Step 2：The chloro- 3-Methoxy Pyridines of the bromo- 2- of 5-
Added into mixture of the bromo- 5- methoxypyridines 1- oxides (2g, 9.80mmol) of 3- in DCM (40mL) POCl3(18.27mL,196mmol).At 40 DEG C, the mixture is stirred 16 hours.The mixture is evaporated, and is distributed in EA (100mL × 2) and the NaHCO of saturation3Between solution (200mL).By the organic extract of merging salt water washing, through MgSO4It is dry It is dry, filter and concentrate.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified.TLC (PE/EA=10 will be passed through:1,Rf =0.6) find that all fractions comprising product merge, and concentrate, obtain the chloro- 3- methoxyl groups of the bromo- 2- of 5- of light yellow oil Pyridine (1g, 4.27mmol, yield 43.6%)：1H NMR(400MHz,CDCl3) δ 8.05 (d, J=2.0Hz, 1H), 7.33 (d, J =2.0Hz, 1H), 3.93 (s, 3H)；ES-LCMS m/z 222.0,224.0(M+H).
Step 3：The bromo- 3-Methoxy Pyridines of 2- (benzyloxy) -5-
It is mixed in phenyl methanol (4.86g, 45.0mmol) to the chloro- 3-Methoxy Pyridines of the bromo- 2- of 5- (1g, 4.50mmol) Sodium (0.310g, 13.49mmol) is added in compound.At 100 DEG C, the mixture is stirred 16 hours.Mixture distribution is existed Between DCM (100mL × 2) and water (80mL).By the organic extract of merging salt water washing, through MgSO4Dry, filter and dense Contracting.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified on.TLC (PE/EA=10 will be passed through:1,Rf=0.6) find All fractions comprising product merge, and concentrate, and obtain the bromo- 3-Methoxy Pyridines of 2- (benzyloxy) -5- of light yellow oil (1.5g, 4.33mmol, yield 96%)：1H NMR(400MHz,CDCl3) δ 7.81 (d, J=2.0Hz, 1H), 7.50-7.48 (m, 2H), 7.31-7.29 (m, 3H), 7.15 (d, J=2.0Hz, 1H), 5.46 (s, 2H), 3.81 (s, 3H)；ES-LCMS m/z 294.0,296.0(M+H)。
Step 4：4- (6- (benzyloxy) -5- methoxypyridine -3- bases) aniline
To the bromo- 3-Methoxy Pyridines of 2- (benzyloxy) -5- (1g, 3.40mmol) in 1,4- dioxanes (30mL) and water (4- aminophenyls) boric acid hydrochloride (0.394mL, 3.74mmol), Cs are added in mixture in (10.0mL)2CO3(4.43g, 13.60mmol) and PdCl2(dppf)(0.249g,0.340mmol).At 110 DEG C, in N2The mixture 16 is stirred under atmosphere small When.Filtration residue, evaporates filtrate, and pass through silica gel column chromatography (PE/EA=5:1) purify.TLC (PE/EA=5 will be passed through:1, Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain 4- (6- (benzyloxy) -5- methoxypyridines -3- Base) aniline (800mg, 2.481mmol, yield 73.0%)：1H NMR(400MHz,CDCl3) δ 7.88 (d, J=2.0Hz, 1H), 7.51 (d, J=7.2Hz, 2H), 7.38-7.30 (m, 5H), 7.22 (d, J=2.0Hz, 1H), 6.78-6.73 (m, 2H), 5.51 (s,2H),3.92(s,3H),3.74(s,2H)；ES-LCMS m/z307.0(M+H).
Step 5：5- (4- aminophenyls) -3-Methoxy Pyridine -2 (1H) -one
At 80 DEG C, stirring 4- (6- (benzyloxy) -5- methoxypyridine -3- bases) aniline (800mg, 2.61mmol) is in salt Mixture in sour (1587 μ l, 52.2mmol) 16 hours.Reaction residue is concentrated, 5- (4- aminophenyls) -3- methoxies are obtained Yl pyridines -2 (1H) -one (500mg, 2.312mmol, yield 89%)：1H NMR(400MHz,CD3OD)δ7.67-7.62(m, 4H), 7.32 (d, J=8.4Hz, 2H), 3.84 (s, 3H)；ES-LCMS m/z 217.2(M+H).
Step 6：1- (4- (5- methoxyl group -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 3- (4- isocyanatos -2- (trifluoromethyl) phenoxy group -3- methy oxetanes (250mg, 0.915mmol) In mixture in THF (10mL) add 5- (4- aminophenyls) -3-Methoxy Pyridine -2 (1H) -one (218mg, 1.007mmol) and Et3N(0.255mL,1.830mmol).At 60 DEG C, the mixture is stirred 1 hour.Then, concentration reaction Residue, and by preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying, obtain the 1- (4- of pink solid (5- methoxyl group -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) - 3- (trifluoromethyl) phenyl) urea (131.55mg, 0.269mmol, yield 29.4%)：1H NMR(400MHz,CD3OD)δ7.80 (d, J=2.8Hz, 1H), 7.58-7.57 (m, 1H), 7.56-7.53 (m, 4H), 7.35 (d, J=2.0Hz, 1H), 7.31 (d, J =2Hz, 1H), 6.65 (d, J=9.2Hz, 1H), 4.93 (d, J=6.8Hz, 2H), 4.66 (d, J=7.2Hz, 2H), 3.95 (s, 3H),1.75(s,3H)；ES-LCMS m/z 490.1(M+H).
Embodiment 22：1- (the fluoro- 4- of 2- (4- oxo -2,3,4,5- tetrahydrofurans [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：(E) -3- (furans -2- bases) acrylic acid
At room temperature, to furans -2- formaldehyde (30g, 312mmol) and malonic acid (35.7g, 343mmol) in pyridine Piperidines (3.09mL, 31.2mmol) is added in mixture in (300mL), and at 100 DEG C, stirs the mixture 16 hours. Reaction solution is poured into water (200mL), and is acidified with 6M hydrochloric acid.Obtained sediment is collected by filtration, obtain (E)- 3- (furans -2- bases) acrylic acid (32g, 227mmol, yield 72.7%)：1H NMR(400MHz,CD3OD) δ 7.61 (d, J= 1.6Hz, 1H), 7.42 (d, J=15.6Hz, 1H), 6.73 (d, J=3.2Hz, 1H), 6.53 (dd, J=2.0,3.6Hz, 1H), 6.22 (d, J=15.6Hz, 1H)；ES-LCMS m/z 139.1(M+H).
Step 2：(E) -3- (furans -2- bases) acryloyl group azide
Under ice-cooling, to (E) -3- (furans -2- bases) acrylic acid (25g, 181mmol) and Et3N(30.3mL, DPPA (54.8g, 199mmol) 217mmol) is added in the mixture in THF (50mL).At 25 DEG C, the mixture 4 is stirred Hour.Reaction solution is poured into EA (300mL) and the NaHCO of saturation3In the mixture of the aqueous solution (300mL), and use EA (200mL) extracts the mixture.Through anhydrous Na2SO4Dry extract, and evaporation solvent under reduced pressure.Remnants are washed with MeOH Thing, obtains (E) -3- (furans -2- bases) acryloyl group azide (24g, 144mmol, yield 80%)：1H NMR(400MHz, CDCl3) δ 7.53-7.50 (m, 1H), 7.47 (s, 1H), 6.71 (d, J=3.2Hz, 1H), 6.50 (dd, J=2.0,3.6Hz, 1H), 6.30 (d, J=3.6Hz, 1H).
Step 3：Furans simultaneously [3,2-c] pyridine -4 (5H) -one
At 100 DEG C, stirring (E) -3- (furans -2- bases) acryloyl group azide (10g, 61.3mmol) is in toluene Mixture in (100mL) 30 minutes.Evaporation solvent.Residue is dissolved in 1,2- dichloro-benzenes (90g, 613mmol) and iodine In (0.062g, 0.245mmol).At 180 DEG C, the mixture is stirred 2 hours.Evaporation solvent.Residue is dissolved in MeOH In (200mL).Sediment is filtered out, filtrate is concentrated, and is washed with TBME (50mL), furans simultaneously [3,2-c] pyridine -4 is obtained (5H) -one (5g, 31.5mmol, yield 51.3%)：1H NMR(400MHz,CD3OD) δ 7.71 (d, J=2.0Hz, 1H), 7.32 (d, J=7.2Hz, 1H), 6.95 (dd, J=1.2,2.4Hz, 1H), 6.75 (dd, J=0.8,7.2Hz, 1H)；ES-LCMS m/z 136.1(M+H)。
Step 4：7- bromines furans simultaneously [3,2-c] pyridine -4 (5H) -one
At 0 DEG C, through 10 minutes, to furans simultaneously [3,2-c] pyridine -4 (5H) -one (5g, 37.0mmol) in MeCN Solution of the NBS (8.56g, 48.1mmol) in MeCN is added in mixture in (50mL).At 0 DEG C, it is outstanding that stirring is obtained Supernatant liquid 1 hour, and it is warming up to room temperature 10 minutes.Water (250mL) and the NaHCO of saturation are added into the mixture3The aqueous solution (10mL).Be collected by filtration white-yellowish solid, and dry, obtain 7- bromines furans simultaneously [3,2-c] pyridine -4 (5H) -one (1.5g, 5.96mmol, yield 16.10%)：1H NMR(400MHz,CD3OD) δ 7.82 (d, J=2.0Hz, 1H), 7.51 (s, 1H), 7.05 (d, J=2.4Hz, 1H)；ES-LCMS m/z 214.0,215.9(M+H).
Step 5：1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 7- bromines furans simultaneously [3,2-c] pyridine -1 (5H) -one (250mg, 1.168mmol) in 1,4- dioxanes (3mL) and 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) are added in mixture in water (1mL) Phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (656mg, 1.285mmol)、PdCl2(dppf) (85mg, 0.117mmol) and Cs2CO3(761mg,2.336mmol).Under microwave, in N2 The mixture is stirred in 110 DEG C under atmosphere 30 minutes.The mixture is filtered, and concentrates filtrate.By preparing TLC (DCM/MeOH =15:1, Rf=residue 0.6) is purified, obtain 1- (the fluoro- 4- of 2- (4- oxos -4,5- dihydrofuran simultaneously [3,2- of yellow solid C] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (45mg, 0.082mmol, yield 7.00%)：1H NMR(400MHz,CD3OD) δ 8.20 (t, J=8.8Hz, 1H), 7.84 (d, J =2.0Hz, 1H), 7.80 (d, J=2.8Hz, 1H), 7.61-7.51 (m, 4H), 7.06 (d, J=2.4Hz, 1H), 6.62 (d, J =9.2Hz, 1H), 4.89 (d, J=6.8Hz, 2H), 4.63 (d, J=7.2Hz, 2H), 1.72 (s, 3H)；ES-LCMS m/z 518.0(M+H)。
Step 6：1- (the fluoro- 4- of 2- (4- oxo -2,3,4,5- tetrahydrofurans [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (30mg, 0.058mmol) mixing in MeOH (10mL) Pd/C (3mg, 0.028mmol) is added in compound.At 25 DEG C, in H2The mixture is stirred under atmosphere 48 hours.It will react residual Excess is filtered and concentrated.By preparing HPLC (MeCN/H2O is used as eluent, alkalescence condition) purifying residue, obtain white solid 1- (the fluoro- 4- of 2- (4- oxo -2,3,4,5- tetrahydrofurans [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methyl oxygen of body Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (17.18mg, 0.032mmol, yield 55.6%)：1H NMR (400MHz,CD3OD) δ 8.14 (t, J=8.4Hz, 1H), 7.81 (d, J=2.4Hz, 1H), 7.57-7.56 (m, 2H), 7.45 (d, J=12.8Hz, 1H), 7.36 (d, J=7.6Hz, 1H), 6.65 (d, J=9.2Hz, 1H), 4.92 (d, J=6.4Hz, 2H), 4.65 (d, J=7.2Hz, 2H), 4.60 (s, 2H), 3.15 (t, J=9.2Hz, 2H), 1.75 (s, 3H)；ES-LCMS m/z 520.0(M+H)。
Embodiment 23：1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile
NaH is added into 2- (2- (trifluoromethyl) phenyl) mixture of acetonitrile (5g, 27.0mmol) in DMF (50mL) (1.620g, 67.5mmol) and MeI (4.22mL, 67.5mmol).At 25 DEG C, the mixture is stirred 16 hours.Use water (100mL) washs the mixture, and is extracted with DCM (120mL × 2).By the organic extract of merging salt water washing, warp MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified.TLC (PE/EA=will be passed through 10:1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain the 2- methyl -2- (2- of light yellow oil (trifluoromethyl) phenyl) propionitrile (4.8g, 19.14mmol, yield 70.9%)：1H NMR(400MHz,CD3OD)δ7.83(dd,J =8.4,14.4Hz, 1H), 7.70 (t, J=8.0Hz, 1H), 7.62-7.54 (m, 1H), 1.89 (s, 6H)；ES-LCMS m/z 214.1(M+H)。
Step 2：2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile
To 2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile (4.8g, 22.51mmol) in H2SO4(22.08g, Nitro peracid potassium (2.73g, 27.0mol) is added in mixture in 225mmol).At 0 DEG C, the mixture is stirred 15 minutes. The mixture is extracted with EA (50mL × 2), and is washed with water (50mL), organic layer is obtained.By the organic extract salt of merging Water washing, through Na2SO4Dry, concentration obtains the 2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) of light yellow oil Propionitrile (5g, 17.04mmol, yield 76%)：1H NMR(400MHz,CD3OD) δ 8.66 (d, J=2.4Hz, 1H) 8.53 (dd, J =2.4,9.2Hz, 1H) 8.11 (d, J=9.2Hz, 1H) 1.95 (s, 6H)；ES-LCMS m/z 259.0(M+H).
Step 3：2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile
To 2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile (8g, 31.0mmol) in MeOH (100mL) Mixture in add Pd/C (800mg, 10%).At 25 DEG C, the mixture is stirred 15 hours.Filter the mixture and dense Contracting.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA= 3:1) residue is purified.TLC (PE/EA=3 will be passed through:1,Rf=0.6) find that all fractions comprising product merge, and it is dense Contracting, obtains 2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile (6.7g, 24.95mmol, yield of red oil 81%)：1H NMR(400MHz,CD3OD) δ 7.39 (d, J=8.8Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 6.84 (dd, J= 2.4,8.8Hz,1H),1.77(s,6H)；ES-LCMS m/z 229.1(M+H).
Step 4：1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- ((4- Methoxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (100mg, 0.253mmol) in 1,4- dioxanes (10mL)3N (0.053mL, 0.379mmol) and DPPA (84mg, 0.303mmol).The mixture is stirred at 25 DEG C 15 minutes.Then, 2- (4- ammonia is added into the mixture Base -2- (trifluoromethyl) phenyl) -2- methyl propionitrile (69.3mg, 0.303mmol).At 80 DEG C, the mixture is stirred 2 hours. The mixture is concentrated, and by preparing TLC (DCM/MeOH=20:1,Rf=0.6) purify, obtain the 1- (4- (2- of yellow solid Dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea (100mg, 0.137mmol, yield 54.2%)：1H NMR(400MHz,CD3OD)δ9.09 (s, 1H), 8.66 (d, J=2.0Hz, 1H), 8.07 (d, J=1.6Hz, 1H), 8.01 (d, J=2.0Hz, 1H), 7.77-7.65 (m, 3H), 7.40 (d, J=8.8Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 5.37 (s, 2H), 4.19-4.14 (m, 2H), 3.78 (s, 3H), 2.57 (s, 3H), 1.84 (s, 6H), 1.43 (t, J=7.2Hz, 3H)；ES-LCMS m/z 621.1(M+H).
Step 5：1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxies Base benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) mixing of the urea (100mg, 0.161mmol) in DCM (10mL) TFA (1mL, 12.98mmol) is added in thing.At 25 DEG C, the mixture is stirred 2 hours.NH is added into the mixture4OH (5mL), then concentrates reaction residue.By preparing HPLC (acid conditions；Instrument: DC；Post：Gemini:C18 150* 25mm*10uL；Mobile phase A: water+0.1%HCl；Mobile phase B: MeCN；Flow velocity：25mL/min；Run time: 15min；Gradient Distribution description：25-55 (B%)) purifying residue, obtain 1- (4- (2- dicyanopropane -2- bases) -3- (fluoroforms of yellow solid Base) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea hydrochloride (19.12mg, 0.036mmol, yield 22.10%)：1H NMR(400MHz,CD3OD) δ 9.08 (s, 1H), 8.10 (d, J= 2.0Hz, 1H), 8.02 (d, J=2.4Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 7.76-7.68 (m, 2H), 4.15 (q, J= 7.2Hz, 2H), 2.57 (s, 3H), 1.84 (s, 6H), 1.48 (t, J=7.2Hz, 3H)；ES-LCMS m/z 501.1(M+H).
Embodiment 24：1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile
Added into 2- (2- (trifluoromethyl) phenyl) mixture of acetonitrile (10g, 54.0mmol) in DMF (100mL) MeI (3.38mL, 54.0mmol) and NaH (2.59g, 64.8mmol).At 25 DEG C, the mixture is stirred 16 hours.This is mixed Compound is concentrated, and is washed with water, and extracted with DCM.By the organic extract of merging salt water washing, through MgSO4Dry, filtering is simultaneously Concentration.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find bag All fractions containing product merge, and concentrate, obtain light yellow oil 2- (2- (trifluoromethyl) phenyl) propionitrile (8g, 34.1mmol, yield 63.2%)：1H NMR(400MHz,CD3OD)δ7.87-7.81(m,1H),7.80-7.72(m,2H), 7.61-7.53 (m, 1H), 4.39 (q, J=7.2Hz, 1H), 1.68 (d, J=7.2Hz, 3H).
Step 2：2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile
To 2- (2- (trifluoromethyl) phenyl) propionitrile (8g, 40.2mmol) in H2SO4Mixing in (39.4g, 402mmol) Nitro peracid potassium (4.87g, 48.2) is added in thing.At 0 DEG C, the mixture is stirred 15 minutes.Should with EA (50mL × 2) extractions Mixture, and washed with water (50mL), obtain organic layer.By the organic extract of merging salt water washing, through Na2SO4Dry, Concentration, obtained 2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile and 2- (4- nitros -2- (trifluoromethyl) phenyl) propionamide Light yellow mixture (7.8g, 19.17mmol, yield 47.7%)..TLC (PE/EA=5:1,Rf=0.6):1H NMR (400MHz,CD3OD) δ 8.65-8.58 (m, 2H), 8.15 (d, J=8.4Hz, 1H), 4.55 (q, J=7.2Hz, 1H), 1.73 (d, J=7.2Hz, 3H).
Step 3：2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile
To 2- (4- nitros -2- (trifluoromethyl) phenyl) propionamides (7.8g, 29.7mmol) DCM (100mL) mixing Et is added in thing3N (8.29mL, 59.5mmol) and TFAA (6.30mL, 44.6mmol).At 25 DEG C, the mixture 16 is stirred Hour.The mixture is washed with water.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated. To 2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile (7.5g, 26.1mmol, yield 88%).TLC (PE/EA=5:1,Rf 0.6):1H NMR(400MHz,CD3OD) δ 8.65-8.58 (m, 2H), 8.15 (d, J=8.4Hz, 1H), 4.55 (q, J=7.2Hz, 1H), 1.73 (d, J=7.2Hz, 3H).
Step 4：2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile
To 2- (4- nitros -2- (trifluoromethyl) phenyl) mixture of the propionitrile (9g, 36.9mmol) in MeOH (100mL) Middle addition Pd/C (90mg, 10%).In H2Under atmosphere, at 25 DEG C, the mixture is stirred 16 hours, filtering reaction residue is simultaneously Concentration.Pass through silica gel column chromatography (PE/EA=3:1) residue is purified.TLC (PE/EA=3 will be passed through:1,Rf=0.6) find bag All fractions containing product merge, and concentrate, and obtain 2- (4- amino -2- (trifluoromethyl) phenyl) propionitrile of light yellow oil (7g, 29.4mmol, yield 80%)：1H NMR(400MHz,CD3OD) δ 7.44 (d, J=8.4Hz, 1H), 6.99 (d, J= 2.4Hz, 1H), 6.96-6.92 (m, 1H), 4.19 (q, J=7.2Hz, 1H), 1.59 (d, J=7.2Hz, 3H)；ES-LCMS m/z 215.1(M+H)。
Step 5：1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxyl groups Benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (200mg, 0.506mmol) in 1,4- dioxanes (10mL)3N (0.106mL, 0.759mmol) and DPPA (167mg, 0.607mmol).The mixture is stirred at 25 DEG C 15 minutes.Then, 2- (4- ammonia is added into the mixture Base -2- (trifluoromethyl) phenyl) propionitrile (130mg, 0.607mmol).At 80 DEG C, the mixture is stirred 2 hours.This is concentrated to mix Compound, and by preparing TLC (DCM/MeOH=15:1, Rf=0.6) purify, obtain 1- (4- (the 1- cyano group second of yellow solid Base) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5- bases) urea (10mg, 0.014mmol, yield 2.77%)：1H NMR(400MHz,CD3OD)δ9.19(s,1H),8.26 (s, 1H), 8.00 (s, 1H), 7.78-7.73 (m, 2H), 7.37 (d, J=7.6Hz, 2H), 6.90 (d, J=7.6Hz, 2H), 6.47(s,1H),5.30(s,2H),4.31(m,1H),4.14-4.10(m,2H),3.78(s,3H),2.70(s,3H),1.63 (d, J=6.8Hz, 3H), 1.34 (t, J=7.2Hz, 3H)；ES-LCMS m/z607.1(M+H).
Step 6：1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxybenzyls Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) in mixture of the urea (10mg, 0.016mmol) in DCM (10mL) Add TFA (1mL, 12.98mmol).At 25 DEG C, the mixture is stirred 2 hours.The mixture is concentrated, and adds NH4OH (0.5mL).Then, reaction residue is concentrated, and by preparing HPLC (posts: ASB C18 150*25mm；Mobile phase A: water+ 0.1%HCl；Mobile phase B: MeCN；Flow velocity：25mL/min；Gradient distribution description：32-62 (B%)) purifying, obtain yellow-white and consolidate 1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- of body Base) -4- methylpyrimidine -5- bases) urea hydrochloride (3.14mg, 5.91 μm of ol, yield 35.9%)：1H NMR(400MHz,CD3OD)δ 9.19 (s, 1H), 8.26 (s, 1H), 8.00 (s, 1H), 7.78-7.73 (m, 2H), 7.37 (d, J=8.0Hz, 2H), 6.90 (d, J =8.0Hz, 2H), 6.47 (s, 1H), 5.30 (s, 2H), 4.31 (m, 1H), 4.14-4.10 (m, 2H), 3.78 (s, 3H), 2.70 (s, 3H), 1.63 (d, J=6.8Hz, 3H), 1.34 (t, J=7.2Hz, 3H)；ES-LCMS m/z 487.1(M+H)；TLC (DCM/MeOH=10:1,Rf=0.4).
Embodiment 25：1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile
Added into 2- (2- (trifluoromethyl) phenyl) mixture of acetonitrile (10g, 54.0mmol) in DMF (100mL) MeI (3.38mL, 54.0mmol) and NaH (2.59g, 64.8mmol).At 25 DEG C, the mixture is stirred 16 hours.This is mixed Compound is concentrated, and is washed with water, and extracted with DCM.By the organic extract of merging salt water washing, through MgSO4Dry, filtering is simultaneously Concentration.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find bag All fractions containing product merge, and concentrate, obtain light yellow oil 2- (2- (trifluoromethyl) phenyl) propionitrile (8g, 34.1mmol, yield 63.2%)：1H NMR(400MHz,CD3OD)δ7.87-7.81(m,1H),7.80-7.72(m,2H), 7.61-7.53 (m, 1H), 4.39 (q, J=7.2Hz, 1H), 1.68 (d, J=7.2Hz, 3H).
Step 2：2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile
To 2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile (8g, 40.2mmol) in H2SO4In (39.4g, 402mmol) Mixture in add nitro peracid potassium (4.87g, 48.2mmol).At 0 DEG C, the mixture is stirred 15 minutes.With EA (50mL × mixture 2) is extracted, and washed with water (50mL), obtain organic layer.By the organic extract of merging salt water washing, warp Na2SO4Dry, concentration obtains 2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile and 2- (4- nitros -2- (trifluoromethyl) benzene Base) propionamide light yellow mixture (7.8g, 19.17mmol, yield 47.7%).TLC (PE/EA=5:1,Rf=0.6):1H NMR(400MHz,CD3OD) δ 8.65-8.58 (m, 2H), 8.15 (d, J=8.4Hz, 1H), 4.55 (q, J=7.2Hz, 1H), 1.73 (d, J=7.2Hz, 3H).
Step 3：2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile
To 2- (4- nitros -2- (trifluoromethyl) phenyl) propionamides (7.8g, 29.7mmol) DCM (100mL) mixing Et is added in thing3N (8.29mL, 59.5mmol) and TFAA (6.30mL, 44.6mmol).At 25 DEG C, the mixture 16 is stirred Hour.The mixture is washed with water.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated. To 2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile (7.5g, 26.1mmol, yield 88%).TLC (PE/EA=5:1,Rf 0.6):1H NMR(400MHz,CD3OD) δ 8.65-8.58 (m, 2H), 8.15 (d, J=8.4Hz, 1H), 4.55 (q, J=7.2Hz, 1H), 1.73 (d, J=7.2Hz, 3H)
Step 4：2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile
To 2- (4- nitros -2- (trifluoromethyl) phenyl) mixture of the propionitrile (9g, 36.9mmol) in MeOH (100mL) Middle addition Pd/C (90mg, 10%).In H2Under atmosphere, at 25 DEG C, the mixture is stirred 16 hours, filtering reaction residue is simultaneously Concentration.Pass through silica gel column chromatography (PE/EA=3:1) residue is purified.TLC (PE/EA=3 will be passed through:1,Rf=0.6) find bag All fractions containing product merge, and concentrate, and obtain 2- (4- amino -2- (trifluoromethyl) phenyl) propionitrile of light yellow oil (7g, 29.4mmol, yield 80%)：1H NMR(400MHz,CD3OD) δ 7.44 (d, J=8.5Hz, 1H), 6.99 (d, J= 2.4Hz, 1H), 6.96-6.92 (m, 1H), 4.19 (q, J=7.2Hz, 1H), 1.59 (d, J=7.2Hz, 3H)；ES-LCMS m/z 215.1(M+H)。
Step 5：1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxyl groups Benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (100mg, 0.253mmol) in 1,4- dioxanes (10mL)3N (0.053mL, 0.379mmol) and DPPA(84mg,0.303mmol).At 25 DEG C, the mixture is stirred 15 minutes.Then, 2- (4- ammonia is added into the mixture Base -2- (trifluoromethyl) phenyl) propionitrile (65.0mg, 0.303mmol).At 80 DEG C, the mixture is stirred 2 hours.Concentration should Mixture, and by preparing TLC (DCM/MeOH=20:1,Rf=0.6) purify, obtain 1- (4- (the 1- cyano group second of yellow solid Base) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5- bases) urea (100mg, 0.132mmol, yield 52.1%)：1H NMR(400MHz,CD3OD)δ9.09(s,1H),8.67 (d, J=2.0Hz, 1H), 8.08 (d, J=1.6Hz, 1H), 7.99 (s, 1H), 7.77-7.69 (m, 3H), 7.40 (d, J= 8.8Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 5.38 (s, 2H), 4.19-4.14 (m, 2H), 4.14-4.10 (m, 1H), 3.78 (s, 3H), 2.57 (s, 3H), 1.63 (d, J=7.2Hz, 3H), 1.43 (t, J=7.2Hz, 3H)；ES-LCMS m/z 607.1(M +H)。
Step 6：1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxybenzyls Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) in mixture of the urea (100mg, 0.165mmol) in DCM (10mL) Add TFA (1mL, 12.98mmol).At 25 DEG C, the mixture is stirred 2 hours.Add NH4OH (5mL), and concentrate mixing Thing.By preparing HPLC (acid conditions；Post: ASB C18 150*25mm；Mobile phase A: water+0.1%HCl；Mobile phase B: MeCN；Flow velocity：25mL/min；Run time: 15min；Gradient distribution description：36-66 (B%)) purifying residue, obtain yellow Solid 1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines - 3- yls) -4- methylpyrimidine -5- bases) urea hydrochloride (18.56mg, 0.035mmol, yield 21.41%)：1H NMR(400MHz, CD3OD) δ 9.13 (s, 1H), 8.12 (d, J=2.4Hz, 1H), 8.01 (s, 1H), 7.87 (d, J=2.0Hz, 1H), 7.76- 7.71 (m, 2H), 4.31 (q, J=7.2Hz, 1H), 4.16 (q, J=6.8Hz, 2H), 2.60 (s, 3H), 1.63 (d, J= 7.2Hz, 3H), 1.48 (t, J=7.2Hz, 3H)；ES-LCMS m/z 487.1(M+H).
Embodiment 26：1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile
NaH is added into 2- (2- (trifluoromethyl) phenyl) mixture of acetonitrile (5g, 27.0mmol) in DMF (50mL) (1.620g, 67.5mmol) and MeI (4.22mL, 67.5mmol).At 25 DEG C, the mixture is stirred 16 hours.This is mixed Thing is washed with water (100mL), and is extracted with DCM (120mL × 2).By the organic extract of merging salt water washing, through MgSO4 It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10:1) residue is purified on.TLC (PE/EA=10 will be passed through: 1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain the 2- methyl -2- (2- (three of light yellow oil Methyl fluoride) phenyl) propionitrile (4.8g, 19.14mmol, yield 70.9%)：1H NMR(400MHz,CD3OD) δ 7.83 (dd, J= 8.4,14.4Hz, 1H), 7.70 (t, J=8.0Hz, 1H), 7.62-7.54 (m, 1H), 1.89 (s, 6H)；ES-LCMS m/z 214.1(M+H)。
Step 2：2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile
To 2- methyl -2- (2- (trifluoromethyl) phenyl) propionitrile (4.8g, 22.51mmol) in H2SO4(22.08g, Nitro peracid potassium (2.73g, 27.0mol) is added in mixture in 225mmol).At 0 DEG C, the mixture is stirred 15 minutes. The mixture is extracted with EA (50mL × 2), and is washed with water (50mL), organic layer is obtained.By the organic extract salt of merging Water washing, through Na2SO4Dry, concentration obtains the 2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) of light yellow oil Propionitrile (5g, 17.04mmol, yield 76%)：1H NMR(400MHz,CD3OD) δ 8.66 (d, J=2.4Hz, 1H), 8.53 (dd, J =2.4,9.2Hz, 1H), 8.11 (d, J=9.2Hz, 1H), 1.95 (s, 6H)；ES-LCMS m/z 259.0(M+H).
Step 3：2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile
To 2- methyl -2- (4- nitros -2- (trifluoromethyl) phenyl) propionitrile (8g, 31.0mmol) in MeOH (100mL) Mixture in add Pd/C (800mg, 10%).In H2Under atmosphere, at 25 DEG C, the mixture is stirred 15 hours.Filtering should Mixture is simultaneously concentrated.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silicagel column color Compose (PE/EA=3:1) residue is purified.TLC (PE/EA=3 will be passed through:1,Rf=0.6) find to include all fractions of product Merge, and concentrate, obtain red oil 2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile (6.7g, 24.95mmol, yield 81%)：1H NMR(400MHz,CD3OD) δ 7.39 (d, J=8.8Hz, 1H), 7.05 (d, J=2.4Hz, 1H), 6.84 (dd, J=2.4,8.8Hz, 1H), 1.77 (s, 6H)；ES-LCMS m/z 229.1(M+H).
Step 4：1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- ((4- Methoxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (200mg, 0.506mmol) in 1,4- dioxanes (10mL)3N (0.106mL, 0.759mmol) and DPPA (167mg, 0.607mmol).The mixture is stirred at 25 DEG C 15 minutes.Then, 2- (4- ammonia is added into the mixture Base -2- (trifluoromethyl) phenyl) -2- methyl propionitrile (139mg, 0.607mmol).At 80 DEG C, the mixture is stirred 2 hours. The mixture is concentrated, and by preparing TLC (DCM/MeOH=15:1,Rf=0.6) purify, obtain the 1- (4- (2- of yellow solid Dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea (10mg, 0.014mmol, yield 2.71%)：1H NMR(400MHz,CD3OD)δ9.19(s, 1H), 8.27 (s, 1H), 8.00 (s., 1H), 7.76 (d, J=8.4Hz, 1H), 7.71-7.67 (m, 1H), 7.37 (d, J= 8.0Hz, 2H), 6.90 (d, J=8.0Hz, 2H), 6.47 (s, 1H), 5.30 (s, 2H), 4.14-4.10 (m, 2H), 3.78 (s, 3H), 2.57 (s, 3H), 1.84 (s, 6H), 1.34 (t, J=7.2Hz, 3H)；ES-LCMS m/z 501.2(M-PMB+H).
Step 5：1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxies Base benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) mixing of the urea (10mg, 0.016mmol) in DCM (10mL) TFA (1mL, 12.98mmol) is added in thing.At 25 DEG C, the mixture is stirred 2 hours.The mixture is concentrated, and is added NH4OH(1mL).By preparing HPLC (instrument: DC；Post：Gemini:C18 150*25mm*10uL；Mobile phase A: water+0.1% HCl；Mobile phase B: MeCN；Flow velocity：25mL/min；Run time: 15min；Gradient distribution description：30-60 (B%)) purifying it is residual Excess, obtain white-yellowish solid 1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea hydrochloride (5.81mg, 10.28 μm of ol, yield 63.8%)：1H NMR(400MHz,CD3OD)δ9.48(s,1H),8.33(s,1H),8.08(s,1H),7.76-7.71(m,2H), 6.13 (s, 1H), 4.32 (q, J=6.8Hz, 2H), 2.74 (s, 3H), 1.85 (s, 6H), 1.46 (t, J=6.8Hz, 3H)；ES- LCMS m/z 501.1(M+H)。
Embodiment 27：1- (5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 2- isocyanatos pyridines of 5-
Triphosgene is added into mixture of the 5- bromopyridine -2- amine (900mg, 5.20mmol) in THF (20mL) (509mg,1.717mmol).At 60 DEG C, the mixture is stirred 1 hour.LCMS display reactions are completed.The mixture is concentrated, is obtained To the bromo- 2- isocyanatos pyridines of 5- (912mg, 3.97mmol, yield 76%).
Step 2：1- (5- bromopyridine -2- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (fluoroforms Base) phenyl) urea
Et is added into mixture of the bromo- 2- isocyanatos pyridines (500mg, 2.51mmol) of 5- in THF (20mL)3N (0.700mL, 5.03mmol) and 4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) aniline (621mg, 2.51mmol).Under 60, the mixture is stirred 12 hours.LCMS display reactions are completed.The mixture is concentrated, and passes through post color Compose (PE/EA=2：1, Rf0.2) purify, obtain 1- (5- bromopyridine -2- bases) -3- (4- ((3- methy oxetane -3- bases) Epoxide) -3- (trifluoromethyl) phenyl) urea (426mg, 0.834mmol, yield 33.2%).1H NMR(400MHz,CD3OD)8.34 (d, J=2.0Hz, 1H), 7.83 (dd, J=2.4,8.8Hz, 2H), 7.61 (dd, J=2.4,9.2Hz, 1H), 7.25 (d, J= 8.4Hz, 1H), 6.67 (d, J=8.8Hz, 1H), 4.89 (d, J=6.8Hz, 2H), 4.63 (d, J=7.2Hz, 2H), 1.72 (s, 3H)；ES-LCMS m/z 446.0(M+H).
Step 3：1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide)-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
In N2Under, to 1- (5- bromopyridine -2- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoros Methyl) phenyl) 3- ethoxies are added in mixture of the urea (200mg, 0.448mmol) in 1,4- dioxanes (3ml) and water (1ml) Base -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (173mg,0.448mmol)、PdCl2(dppf) (32.8mg, 0.045mmol) and Cs2CO3(292mg,0.896mmol).Micro- Under ripple, the mixture is stirred at 110 DEG C 30 minutes.LCMS display reactions are completed.The mixture is filtered, filtrate is concentrated, and lead to Cross TLC (DCM/MeOHc=30:1, Rf0.3) purify, obtain 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) - [3,3'- bipyridyls] -6- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (112mg, 0.157mmol, yield 35.0%).1H NMR(400MHz,CDCl3) 8.38 (d, J=2.0Hz, 1H), 7.83 (d, J =2.0Hz, 1H), 7.75 (d, J=2.4Hz, 2H), 7.73 (d, J=2.8Hz, 1H), 7.37 (d, J=8.4Hz, 2H), 7.12 (d, J=2.0Hz, 1H), 6.84-6.82 (m, 2H), 6.76 (d, J=8.4Hz, 1H), 6.39 (d, J=9.2Hz, 1H), 5.39 (s, 2H), 4.92 (d, J=6.4Hz, 2H), 4.52 (d, J=7.2Hz, 2H), 4.09 (d, J=6.8Hz, 2H), 3.74 (s, 3H), 1.68 (s, 3H), 1.43 (t, J=7.2Hz, 3H)；ES-LCMS m/z625.1(M+H).
Step 4：1- (5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide)-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (100mg, 0.160mmol) is in MeOH (5mL) Pd/C (17.04mg, 0.160mmol) is added in mixture.In H2Under, the mixture is stirred at 20 DEG C 12 hours.LCMS shows Show that reaction is completed.Filter the mixture, concentrate filtrate, and purified by HPLC, obtain 1- (5'- ethyoxyl -6'- oxo -1', 6'- dihydros-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene Base) urea (31.83mg, 0.063mmol, yield 39.4%).1H NMR(400MHz,DMSO-d6)11.80(s,1H),10.43(s, 1H), 9.46 (s, 1H), 8.50 (d, J=2.4Hz, 1H), 7.97 (dd, J=2.4,8.8Hz, 1H), 7.88 (d, J=2.8Hz, 1H), 7.57-7.50 (m, 2H), 7.28 (d, J=2.4Hz, 1H), 7.12 (d, J=2.4Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 4.72 (d, J=6.8Hz, 2H), 4.57 (d, J=7.2Hz, 2H), 4.02 (d, J=6.8Hz, 2H), 1.63 (s, 3H), 1.32 (t, J=6.8Hz, 3H)；ES-LCMS m/z 505.0(M+H).
Embodiment 28：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea
Step1：1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (4- ethyoxyls -6- ((4- methoxyl groups Benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
At 20 DEG C, to 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Carboxylic acid (0.2g, 0.506mmol) adds Et in the mixture in 1,4- dioxanes (10ml)3N(0.102g,1.012mmol)、 DPPA (0.209g, 0.759mmol) and 1- (5- amino -3- (trifluoromethyl) pyridine -2- bases) ethyl ketone (0.103g, 0.506mmol).At 80 DEG C, the mixture is stirred 2 hours.TLC (DCM/MeOH=15:1, Rf0.3) shown instead with LCMS It should complete.The mixture is concentrated, and passes through TLC (DCM/MeOH=15:1, Rf 0.3) purify, obtain 1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by -3- Pyridine -5- bases) urea (45mg, 0.075mmol, yield 14.91%)：1H NMR(400MHz,CD3OD)8.55(s.,1H),8.31- 8.24 (m, 1H), 8.08 (d, J=1.2Hz, 1H), 7.36 (d, J=5.6Hz, 2H), 6.87-6.83 (m, 3H), 6.43 (s, 1H), 5.30 (s, 2H), 4.12 (d, J=6.6Hz, 2H), 3.76 (s, 3H), 2.64 (s, 3H), 2.40 (s, 3H), 1.33 (d, J =1.5Hz, 3H)；ES-LCMS m/z 597.2(M+H).
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea
At 0 DEG C, to 1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (4- ethyoxyls -6- ((4- first Oxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (22mg, 0.037mmol) mixing in THF (10mL) MeMgBr (0.111mL, 0.111mmol) is added in compound.Stir the mixture 1 hour.TLC (DCM/MeOH=15:1,Rf 0.4) display reaction is completed.Use H2Reaction is quenched in O (0.2mL) and HCl/water solution (0.1mL, 1N).The mixture is filtered, is dried Filtrate, concentrates in a vacuum, and passes through TLC (DCM/MeOH=10:1,Rf0.2) with preparation HPLC purifying residues, 1- is obtained (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propanes -2- Base) -5- (trifluoromethyl) pyridin-3-yl) urea (2.07mg, 4.18 μm of ol, yield 11.32%)：1H NMR(400MHz,CD3OD) 9.14 (s, 1H), 8.75 (d, J=2.4Hz, 1H), 8.40 (d, J=2.4Hz, 1H), 7.79 (s, 1H), 5.99 (s, 1H), 4.11 (t, J=7.2Hz, 2H), 2.56 (s, 3H), 1.60 (s, 6H), 1.37 (t, J=7.2Hz, 3H)；ES-LCMS m/z 493.1(M +H)。
Embodiment 29：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea
Step1：1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (5- ethyoxyls -6- ((4- methoxyl groups Benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
At 20 DEG C, to 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Carboxylic acid (adds Et in the mixture in 0.2g, 0.506mmol) dioxanes (10ml)3N(0.102g,1.012mmol),、 DPPA (0.209g, 0.759mmol) and 1- (5- amino -3- (trifluoromethyl) pyridine -2- bases) ethyl ketone (0.103g, 0.506mmol).At 80 DEG C, the mixture is stirred 2 hours.TLC (DCM/MeOH=15:1,Rf0.3) shown instead with LCMS It should complete.The mixture is concentrated in a vacuum, and passes through TLC (DCM/MeOH=15:1, Rf 0.3) residue is purified, 1- is obtained (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea (50mg, 0.064mmol, yield 12.68%)：1H NMR(400MHz,CD3OD)8.53(s, 1H), 8.08 (d, J=1.7Hz, 1H), 7.41-7.40 (m, 2H), 7.24 (d, J=8.6Hz, 2H), 6.91-6.87 (m, 3H), 5.38 (s, 2H), 4.15 (d, J=2.7Hz, 2H), 3.76 (s, 3H), 2.63 (s, 3H), 2.59 (s, 3H), 1.45 (d, J= 2.0Hz,3H)；ES-LCMS m/z 597.1(M+H).
Step 2：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea
At 20 DEG C, to 1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (5- ethyoxyls -6- ((4- first Oxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (50mg, 0.084mmol) mixing in THF (10mL) MeMgBr (0.251mL, 0.251mmol) is added in compound.Stir the mixture 1 hour.TLC (DCM/MeOH=10:1,Rf= 0.5) display reaction is completed.Reaction is quenched with water (0.3mL).Mixture is filtered, filtrate is concentrated in a vacuum, and pass through TLC (DCM/MeOH=10:1,Rf0.5) residue is purified, 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyrroles are obtained Pyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea (20mg, 0.023mmol, yield 27.4%)：1H NMR(400MHz,CD3OD) 8.41 (t, J=2.3Hz, 1H), 8.07 (dd, J =1.8,4.8Hz, 1H), 7.85 (d, J=2.0Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.25 (d, J=8.6Hz, 2H), 6.89-6.85(m,3H),5.37(s,2H),4.19-4.12(m,2H),3.80(s,3H),2.59(s,3H),1.59(s,6H), 1.49-1.42(m,3H)；ES-LCMS m/z 493.1(M-PMB+H).
Step 3：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea
In N2Under, to 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines - 5- yls) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea (20mg, 0.033mmol) is in MeOH Pd/C (3.47mg, 0.033mmol, 10%) is added in mixture in (10mL).In H2Under atmosphere, the mixture 1 is stirred small When.LCMS and TLC (DCM/MeOH=10:1, Rf=0.3) display reaction completion.The mixture is filtered, and by preparing HPLC Filtrate is purified, 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- are obtained (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea (3.91mg, 7.83 μm of ol, yield 23.97%)：1H NMR(400MHz,CD3OD) 9.01 (s, 1H), 8.74 (d, J=2.4Hz, 1H), 8.40 (d, J=2.4Hz, 1H), 8.07 (d, J =2.0Hz, 1H), 7.86 (d, J=2.0Hz, 1H), 4.16-4.11 (m, 2H), 2.55 (s, 3H), 1.60 (s, 6H), 1.48 (t, J=6.8Hz, 3H)；ES-LCMS m/z 493.1(M+H).
Embodiment 30：1- (2- (difluoromethyl) -4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) - 3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
Step 1：4- bromo- 2- (difluoromethyl) -1- nitrobenzene
At 0 DEG C, added into solution of the bromo- 2- nitrobenzaldehydes (0.5g, 2.174mmol) of 5- in DCM (20mL) DAST(0.431mL,3.26mmol).At room temperature, obtained mixture is stirred.After 2 hr, TLC analyzes (PE/EA= 3/1) display initial substance disappears.The mixture is poured into ice.The mixture being obtained by extraction with DCM (50mL).Will be organic Layer is dried and concentrated, and obtains 4- bromo- 2- (difluoromethyl) -1- nitrobenzene (0.5g, 1.936mmol, yield 89%), its:1H NMR(400MHz,CD3OD)δ8.12-8.09(m,1H),8.04-8.03(m,1H),7.96-7.93(m,1H),7.51-7.24 (m,1H)。
Step 2：4- bromo- 2- (difluoromethyl) aniline
Exist to 4- bromo- 2- (difluoromethyl) -1- nitrobenzene (0.5g, 1.984mmol) and zinc (1.297g, 19.84mmol) NH is added in solution in MeOH (30mL)4Cl(1.061g,19.84mmol).At 25 DEG C, obtained mixture mistake is stirred Night.After TLC analyses (PE/EA=3/1) show that initial substance disappears, the mixture is filtered.Filtrate is concentrated, remnants are obtained Thing, is dissolved in EA (60mL), and use H2O (30mL) and salt solution (30mL) washing.By organic layer through Na2SO4Dry, filtering And concentrate.Residue is purified by preparing TLC (PE/EA=3/1), 4- bromo- 2- (difluoromethyl) aniline of yellow solid is obtained (0.26g, 0.713mmol, yield 36.0%)：1H NMR(400MHz,CDCl3)δ7.35(s,1H),7.34-7.31(m,1H), 6.69-6.41 (m, 1H), 6.61 (d, J=8.4Hz, 1H), 4.07 (brs, 2H)；ES-LCMS m/z 221.9,224.0(M+ H)。
Step 3：1- (4- bromo- 2- (difluoromethyl) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoros Methyl) phenyl) urea
Three light are added into solution of 4- bromo- 2- (difluoromethyl) aniline (100mg, 0.450mmol) in THF (10mL) Gas (46.8mg, 0.158mmol).At 70 DEG C, obtained mixture is stirred.After 30 minutes, lcms analysis display starting Material disappears.Remove solvent under vacuo, obtain 4- bromo- 2- (difluoromethyl) -1- isocyanatos benzene (110mg, 0.417mmol, Yield 93%).To 4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) aniline (153mg, 0.532mmol), Et3N The bromo- 2- of 4- are added in the solution of (0.124mL, 0.887mmol) and DMAP (10.84mg, 0.089mmol) in THF (10mL) Solution of (the difluoromethyl) -1- isocyanatos benzene (110mg, 0.444mmol) in THF (10mL).At 70 DEG C, stirring is obtained Mixture.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By preparing TLC (DCM/MeOH =residue 10/1) is purified, obtain 1- (4- bromo- 2- (difluoromethyl) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) of solid Methyl) -3- (trifluoromethyl) phenyl) urea (130mg, 0.172mmol, yield 38.9%)：1H NMR(400MHz,CD3OD)δ 7.86 (s, 1H), 7.75 (d, J=8.8Hz, 1H), 7.67-7.63 (m, 4H), 7.03-6.76 (m, 1H), 3.67 (s, 2H), 3.20-3.18(m,2H),2.96(m,8H),1.30(m,3H)；ES-LCMS m/z 535.1,537.1(M+H).
Step 4：1- (2- (difluoromethyl) -4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) benzene Base) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 110 DEG C, stirring 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls -1,3, 2- dioxaborolan alkane -2- bases) pyridine (72.0mg, 0.187mmol), 1- (4- bromo- 2- (difluoromethyl) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (100mg, 0.187mmol), PdCl2(dppf)- DCM adducts (15.25mg, 0.019mmol) and Cs2CO3(122mg, 0.374mmol) is in 1,4- dioxanes (3ml) and water Solution in (3.00ml) 15 minutes.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By remnants Thing is dissolved in DCM (60mL), and uses H2O (20mL) and salt solution (20mL) washing.By organic layer through Na2SO4Dry, filter and dense Contracting.Residue is purified by preparing TLC (DCM/MeOH=10/1), 1- (2- (difluoromethyl) -4- (5- ethyoxyls -6- are obtained ((4- methoxy-benzyls) epoxide) pyridin-3-yl) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) Phenyl) urea (60mg, 0.063mmol, yield 33.8%)：1H NMR(400MHz,CD3OD)δ7.95-7.88(m,3H),7.75 (m, 2H), 7.67-7.50 (m, 2H), 7.46 (d, J=2.0Hz, 1H), 7.41-7.39 (m, 1H), 6.96-6.90 (m, 3H), 5.36(s,2H),4.17-4.15(m,2H),3.79(s,3H),3.66-3.65(m,2H),3.56-3.55(m,2H),2.70- 2.61 (m, 8H), 1.42 (t, J=7.0Hz, 3H), 1.17 (t, J=7.2Hz, 3H)；ES-LCMS m/z 714.3(M+H).
Step 5：1- (2- (difluoromethyl) -4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (2- (difluoromethyl) -4- (5- ethyoxyls -6- ((4- methoxy-benzyls) oxygen in HCl is stirred Base) pyridin-3-yl) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (60mg, 0.084mmol) the solution in MeOH (10mL, 175mmol).After lcms analysis shows that initial substance disappears.In vacuum Lower removing solvent.By prepare HPLC purify residue, obtain white solid 1- (2- (difluoromethyl) -4- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) Urea dihydrochloride (21.83mg, 0.033mmol, yield 39.0%)：1H NMR(400MHz,CD3OD)δ8.04(s,1H),7.95 (d, J=8.0Hz, 1H), 7.83 (m, 1H), 7.75-7.73 (m, 3H), 7.52-7.50 (m, 2H), 7.10-5.83 (m, 1H), 4.24-4.19 (m, 4H), 3.72-3.26 (m, 8H), 3.12 (m, 2H), 1.49 (t, J=6.8Hz, 3H), 1.37 (t, J= 7.2Hz,3H)；ES-LCMS m/z 594.2(M+H).
Embodiment 31：1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
Step 1：5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- alcohol
At 0 DEG C, to 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls -1,3,2- bis- Oxa- boron heterocycle pentane -2- bases) pyridine (2g, 5.19mmol) and NaHCO3(3.05g, 36.3mmol) is in acetone (60mL) and water Dihydrate (3.12g, 26.0mmol) is added dropwise in solution in (60mL) to stay overnight.Show that initial substance disappears it in lcms analysis Afterwards.Solvent is removed under vacuo.Residue is dissolved in DCM (100mL), and uses H2O (30mL) and salt solution (30mL) washing.Will Organic layer is through Na2SO4It is dried, filtered and concentrated.Residue is purified by silica gel column chromatography (PE/EA=3/1), yellow is obtained and consolidates 5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- alcohol (1.3g, 4.72mmol, 91%yield) of body：1H NMR (400MHz,CD3OD) δ 7.35-7.32 (m, 2H), 7.22 (d, J=2.4Hz, 1H), 6.89-6.87 (m, 2H), 6.78 (d, J= 2.4Hz, 1H), 5.19 (s, 2H), 4.04-3.98 (m, 2H), 3.77 (s, 3H), 1.37 (t, J=7.0Hz, 3H)；ES-LCMS m/z 276.1(M+H)。
Step 2：3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4-nitrophenoxy) pyridine
At 70 DEG C, stirring 5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- alcohol (0.3g, 1.090mmol), the fluoro- 4- nitrobenzene (0.161g, 1.144mmol) of 1- and K2CO3(0.301g, 2.179mmol) is in MeCN Solutions overnight in (30mL).After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Residue is molten In DCM (60mL), and use H2O (20mL) and salt solution (20mL) washing.Through Na2SO4Organic layer is dried, filters and concentrates.Pass through Silica gel column chromatography (PE/EA=5/1) purifies residue, obtains 3- ethyoxyls -2- ((4- methoxy-benzyls) oxygen of yellow solid Base) -5- (4-nitrophenoxy) pyridine (0.39g, 0.924mmol, yield 85%)：1H NMR(400MHz,CD3OD)δ8.23 (d, J=9.2Hz, 2H), 7.54 (d, J=2.4Hz, 1H), 7.38 (d, J=8.4Hz, 2H), 7.11-7.07 (m, 3H), 6.90 (d, J=8.4Hz, 2H), 5.33 (s, 2H), 4.06-4.01 (m, 2H), 3.79 (s, 3H), 1.38 (t, J=7.0Hz, 3H)；ES- LCMS m/z 397.1(M+H)。
Step 3：4- ((5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) epoxide) aniline
To 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4-nitrophenoxy) pyridine (390mg, 0.981mmol) and add NH in solution of the zinc (642mg, 9.81mmol) in methanol (80ml)4Cl(525mg, 9.81mmol).At 25 DEG C, obtained mixture is stirred.After lcms analysis shows that initial substance disappears.Filter the mixing Thing.Filtrate is concentrated, is dissolved in DCM (60mL), and use H2O (20mL) and salt solution (20mL) washing.By organic layer through Na2SO4 It is dried, filtered and concentrated.Residue is purified by silica gel column chromatography (PE/EA=2/1), 4- ((5- ethyoxyl -6- ((4- are obtained Methoxy-benzyl) epoxide) pyridin-3-yl) epoxide) aniline (250mg, 0.646mmol, yield 65.9%)：1H NMR (400MHz,CD3OD) δ 7.36-7.34 (m, 2H), 7.27 (d, J=2.4Hz, 1H), 6.91-6.89 (m, 3H), 6.79 (dd, J =6.8,2.4Hz, 2H), 6.77-6.71 (m, 2H), 5.25 (s, 2H), 4.00-3.95 (m, 2H), 3.78 (s, 3H), 1.35 (t, J=7.0Hz, 3H)；ES-LCMS m/z 367.0(M+H).
Step 4：1- (4- ((5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) epoxide) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
To 4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) aniline (60mg, 0.209mmol) in THF Triphosgene (21.69mg, 0.073mmol) is added in solution in (10mL).At 70 DEG C, obtained mixture is stirred.30 After minute, TLC analyses (PE/EA=3/1) show that initial substance disappears.Solvent is removed under vacuo, obtains brown oil 1- ethyls -4- (4- isocyanatos -2- (trifluoromethyl) benzyl) piperazine (65mg, 0.197mmol, yield 94%).To 4- ((5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) epoxide) aniline (50mg, 0.136mmol) and Et3N 1- ethyls -4- (4- isocyanatos -2- (trifluoromethyl) benzyl) is added in the solution of (44mg, 0.4mmol) in THF (10mL) Solution of the piperazine (64.1mg, 0.205mmol) in THF (10mL).At 70 DEG C, obtained mixture is stirred.At LCMS points After analysis shows that initial substance disappears.Solvent is removed under vacuo.Use H2O debris.It is remaining by preparing TLC purifying Thing, obtain the 1- (4- ((5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) epoxide) phenyl) of white solid - 3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (50mg, 0.070mmol, yield 51.2%)：1H NMR(400MHz,CD3OD) δ 7.85 (d, J=2.0Hz, 1H), 7.66-7.64 (m, 2H), 7.42-7.36 (m, 5H), 6.99- 6.95 (m, 3H), 6.89 (dd, J=6.8,2.0Hz, 2H), 5.29 (s, 2H), 4.03-3.98 (m, 2H), 3.79 (s, 3H), 3.69 (s, 2H), 3.31-2.65 (m, 8H), 1.37 (t, J=7.0Hz, 3H), 1.27 (t, J=7.2Hz, 3H)；ES-LCMS m/ z 680.1(M+H)。
Step 5：1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((4- second Base piperazine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (4- ((5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in HCl are stirred Base) epoxide) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (50mg, 0.074mmol) the solution in MeOH (5mL, 20.00mmol).After lcms analysis shows that initial substance disappears.In vacuum Lower removing solvent.Residue is purified by preparing HPLC, 1- (4- ((5- ethyoxyl -6- oxos -1,6- of colorless oil are obtained Dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea disalt Hydrochlorate (34.97mg, 0.054mmol, yield 74.0%)：1H NMR(400MHz,CD3OD) δ 8.02 (d, J=2.4Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.74-7.71 (m, 1H), 7.46-7.44 (dd, J=6.8,2.0Hz, 2H), 7.08 (d, J= 2.8Hz, 1H), 7.01 (dd, J=6.8,2.4Hz, 2H), 6.91 (d, J=2.8Hz, 1H), 4.25 (s, 2H), 4.09-4.04 (m,2H),3.70-3.47(m,8H),3.30-3.19(m,2H),1.44-1.36(m,6H)；ES-LCMS m/z 560.2(M+ H)。
Embodiment 32：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea
Step1：1- ethyls -4- (5- fluoro- 2- (trifluoromethyl) benzyl) piperazine
At 20 DEG C, stirring 5- fluoro- 2- (trifluoromethyl) benzaldehyde (2g, 10.41mmol) and 1- ethyl piperazidines The solution of (1.783g, 15.62mmol) in DCM (60mL).After 2 hr, add NaBH (OAc) 3 (6.62g, 31.2mmol).At 20 DEG C, stir obtained mixture and stay overnight.After lcms analysis shows that initial substance disappears.This is mixed Compound is dissolved in H2In O (30mL), and use NaHCO3The aqueous solution is adjusted to pH 8.By organic layer salt water washing, and through Na2SO4It is dry It is dry.After filtration, filtrate is concentrated, is purified by column chromatography (DCM/MeOH=0 to 20/1), obtains the 1- second of yellow oil Base -4- (5- fluoro- 2- (trifluoromethyl) benzyl) piperazine (3g, 8.74mmol, yield 84%)：1H NMR(400MHz,CD3OD)δ 7.78-7.75(m,1H),7.64-7.62(m,1H),7.21-7.18(m,1H),3.80(s,2H),3.24(br.s.,4H), 3.13 (m, 2H), 2.77 (br.s., 4H), 1.34 (t, J=7.4Hz, 3H)；ES-LCMS m/z 291.1(M+H).
Step 2：1- ethyls -4- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) piperazine
To 1- ethyls -4- (5- fluoro- 2- (trifluoromethyl) benzyl) piperazine (3g, 10.33mmol) in H2SO4(6mL, Nitric acid (0.716g, 11.37mmol) is added in solution in 113mmol).At room temperature, the mixture that stirring is obtained is stayed overnight. At 50 DEG C, the mixture is stirred 2 hours.After TLC analyses (PE/EA=10/1) show that initial substance disappears, this is mixed Thing is adjusted to pH 8 with the NaOH aqueous solution, and is extracted with EA (50mL × 2).By organic layer H2O (50mL) and salt solution (50mL) Washing.Through Na2SO4After drying and filtering, concentrate filtrate, obtain yellow oil 1- ethyls -4- (the fluoro- 4- nitros of 5- - 2- (trifluoromethyl) benzyl) piperazine (2.2g, 6.56mmol, yield 63.5%)：1H NMR(400MHz,CD3OD)δ8.39(d,J =7.2Hz, 1H), 7.92 (d, J=12.8Hz, 1H), 3.75 (s, 2H), 2.60-2.47 (m, 10H), 1.14-1.10 (m, 3H)； ES-LCMS m/z 336.1(M+H)。
Step 3：4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) aniline
To 1- ethyls -4- (fluoro- 4- nitros -2- (trifluoromethyl) benzyls of 5-) piperazines (2.2g, 6.56mmol) and zinc NH is added portionwise in the solution of (4.29g, 65.6mmol) in MeOH (100mL)4Cl(3.51g,65.6mmol).At 20 DEG C Under, stir obtained mixture 12 hours.After lcms analysis shows that initial substance disappears.Filter the mixture.Concentration filter Liquid, by preparing HPLC (mobile phase As: containing 0.05%NH3.H2Water/Mobile phase B of O solution：MeCN/ flow velocitys: 80mL/min/ Detection：UV 220nm/254nm/ posts: Phenomenex Gemini C18250*50mm, 10um/ column temperatures: the distribution of RT/ gradients is retouched State：40-70 (B%)) purify 4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) benzene for obtaining yellow solid Amine (0.7g, 2.265mmol, yield 34.5%)：1H NMR(400MHz,CD3OD) δ 7.31 (d, J=12.8Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 3.51 (s, 2H), 2.74-2.15 (m, 10H), 1.10 (t, J=7.4Hz, 3H)；ES-LCMS m/z 306.1(M+H)。
Step 4：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea
At 70 DEG C, in N2Under atmosphere, stirring 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) - 4- methylpyrimidine -5- carboxylic acids (300mg, 0.759mmol), 4- ((4- ethyl piperazidine -1- bases) methyl) fluoro- 5- (fluoroforms of -2- Base) aniline (232mg, 0.759mmol), DPPA (313mg, 1.138mmol) and Et3N (0.159mL, 1.138mmol) is in 1,4- Solution in dioxane (10ml) 12 hours.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Will Residue is distributed in EA (30mL) and H2Between O (20mL), extracted with EA (30mL × 2).By the organic layer salt solution of merging (20mL) is washed, through Na2SO4It is dried, filtered and concentrated, obtains product, by prepares TLC (DCM/MeOH=15/1, Rf= 0.4) purify, obtain 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl of brown solid Pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (200mg, 0.272mmol, yield 35.9%)：1H NMR(400MHz,CD3OD) δ 9.20 (s, 1H), 8.66 (s, 1H), 8.61 (d, J= 7.6Hz, 1H), 8.07 (s, 1H), 7.58 (d, J=12.0Hz, 1H), 7.41 (d, J=8.8Hz, 2H), 6.92 (d, J= 8.4Hz,2H),5.38(s,2H),4.16(m,2H),3.79(s,3H),3.67(s,2H),3.18(m,3H),3.04-2.87(m, 4H), 2.83-2.52 (m, 7H), 1.44 (t, J=6.8Hz, 3H), 1.27-1.20 (m, 3H)；ES-LCMS m/z 578.2(M+ H-PMB)。
Step 5：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in TFA are stirred Base) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea The solution of (200mg, 0.287mmol) in DCM (5mL, 3.72mmol).After 0.5h, lcms analysis shows starting material Matter disappears.Solvent is removed under vacuo.Residue is dissolved in MeCN, and uses NH3.H2O is adjusted to pH 8.The mixture is concentrated, By preparing HPLC (instruments: the posts of Gilson GX 281/: Gemini 150*25mm*5um/ column temperatures: 30 DEG C/mobile phase: A: contain There is the flow velocity of water B: MeCN/: the 25mL/min/ gradients distribution description of 0.05% ammonia spirit：40-70 (B%)) purifying.In freezing After drying, 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- of white solid are obtained Base) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (40mg, 0.069mmol, yield 24.16%)：1H NMR(400MHz,CD3OD) δ 9.17 (s, 1H), 8.61 (d, J=8.0Hz, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.63 (d, J=12.4Hz, 1H), 4.17 (m, 2H), 3.66 (s, 2H), 2.78-2.38 (m, 13H), 1.51 (t, J= 7.0Hz, 3H), 1.14 (t, J=7.4Hz, 3H)；ES-LCMS m/z 578.3(M+H).
Embodiment 33：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidines -5- Base) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
Step 1：4,6- dimethyl -5- nitro-pyrimidine -2- alcohol
At 0 DEG C, to 4,6- dimethyl pyrimidine -2- alcohol (3g, 24.17mmol) at sulfamic acid (10mL, 24.17mmol) In solution in add nitric acid (1.620mL, 36.2mmol).At room temperature, the mixture that stirring is obtained is stayed overnight.At 0 DEG C, to The NaOH aqueous solution is added in the mixture to adjust to pH 8.Filter the mixture.Concentrate filtrate.The mixture is suspended in In MeOH (200mL), and filter.Filtrate is concentrated, is purified by column chromatography (DCM/MeOH=30/1 to 10/1), yellow is obtained and consolidates 4,6- dimethyl -5- nitro-pyrimidine -2- the alcohol (1.6g, 8.99mmol, yield 37.2%) of body：1H NMR(400MHz,CD3OD)δ 2.51(s,6H)；ES-LCMS m/z170.1(M+H).
Step 2：The chloro- 4,6- dimethyl -5- nitro-pyrimidines of 2-
To 6- dimethyl -5- nitro-pyrimidine -2- alcohol (0.5g, 2.96mmol) is in POCl3It is molten in (5mL, 53.8mmol) N, accelerine (0.036g, 0.296mmol) are added in liquid.At 60 DEG C, stir obtained mixture and stay overnight.In LCMS After analysis shows that initial substance disappears.Solvent is removed under vacuo.Residue is added in frozen water, and uses Na2CO3It is water-soluble Liquid is adjusted to pH 8.Filter the mixture.Purified by filtration cakes torrefaction, and by column chromatography (PE/EA=3/1), obtain 2- chloro- 4, 6- dimethyl -5- nitro-pyrimidines (130mg, 0.606mmol, yield 20.52%)：1H NMR(400MHz,CD3OD)δ2.54(s, 6H)；ES-LCMS m/z 188.1(M+H).
Step 3：The chloro- 4,6- dimethyl pyrimidines -5- amine of 2-
Exist to the chloro- 4,6- dimethyl -5- nitro-pyrimidines (130mg, 0.693mmol) of 2- and zinc (45.3mg, 0.693mmol) NH is added in solution in MeOH (20mL)4Cl(37.1mg,0.693mmol).At 25 DEG C, obtained mixture mistake is stirred Night.After lcms analysis shows that initial substance disappears.Filter the mixture.Filtrate is concentrated, passes through column chromatography (PE/EA=3/1 To 1/1) purifying, chloro- 4, the 6- dimethyl pyrimidines -5- amine of 2- (80mg, 0.508mmol, yield 73.2%) of white solid is obtained ：1H NMR(400MHz,CD3OD)δ2.33(s,6H)。
Step 4：1- (the chloro- 4,6- dimethyl pyrimidines -5- bases of 2-) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (three Methyl fluoride) phenyl) urea
Three are added into solution of the chloro- 4,6- dimethyl pyrimidines -5- amine (50mg, 0.317mmol) of 2- in THF (10mL) Phosgene (33.0mg, 0.111mmol).At 70 DEG C, obtained mixture is stirred.Show that initial substance disappears it in lcms analysis Afterwards.Solvent is removed under vacuo, obtains 2- chloro- 5- isocyanatos -4,6- dimethyl pyrimidine (50mg, 0.257mmol, yield 81%).To 4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) aniline (94mg, 0.327mmol) and Et3N The chloro- 5- isocyanatos -4,6- dimethyl pyrimidines of 2- are added in the solution of (0.114mL, 0.817mmol) in THF (10mL) The solution of (50mg, 0.272mmol) in THF (10mL).At 70 DEG C, obtained mixture is stirred.Shown in lcms analysis After initial substance disappears, solvent is removed under vacuo.Residue is dissolved in DCM (60mL), and uses H2O (20mL) and salt solution (20mL) is washed.Through Na2SO4Organic layer is dried, filters and concentrates.It is remaining by preparing HPLC (DCM/MeOH=10/1) purifying Thing, obtains 1- (chloro- 4, the 6- dimethyl pyrimidines -5- bases of 2-) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- of white solid (trifluoromethyl) phenyl) urea (80mg, 0.167mmol, yield 61.2%)：1H NMR(400MHz,CD3OD)δ7.88(s,1H), 7.39 (d, J=8.0Hz, 1H), 6.99 (d, J=2.8Hz, 1H), 3.75 (s, 2H), 3.04 (m, 8H), 2.49 (m, 8H), 1.37 (m,3H)；ES-LCMS m/z471.0(M+H).
Step 5：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4,6- dimethyl pyrimidines - 5- yls) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 110 DEG C, stirring 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyls -1,3, 2- dioxaborolan alkane -2- bases) pyridine (40.9mg, 0.106mmol), 1- (the chloro- 4,6- dimethyl pyrimidines -5- bases of 2-) - 3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (50mg, 0.106mmol), PdCl2(dppf)- DCM adducts (8.67mg, 10.62 μm of ol) and Cs2CO3(69.2mg, 0.212mmol) is in 1,4- dioxanes (3ml) and water Solution in (1ml).After lcms analysis shows that initial substance disappears.The mixture is dissolved in EA (60mL), and uses H2O (20mL) and salt solution (20mL) are washed.Through Na2SO4Organic layer is dried, filters and concentrates.By preparing TLC (DCM/MeOH=10/ 1) purify residue, obtain white solid 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4, 6- dimethyl pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (20mg, 0.024mmol, yield 22.77%)：1H NMR(400MHz,CD3OD) δ 8.71 (d, J=2.0Hz, 1H), 8.12 (d, J= 1.6Hz, 1H), 7.85 (s, 1H), 7.66 (m, 2H), 7.40 (d, J=8.4Hz, 2H), 6.91 (d, J=8.4Hz, 2H), 5.39 (s,2H),4.19-4.14(m,2H),3.78(s,3H),3.66(s,2H),2.81-2.62(m,10H),2.53(s,6H),1.43 (t, J=7.0Hz, 3H), 1.21 (t, J=7.2Hz, 3H)；ES-LCMS m/z 694.2(M+H).
Step 6：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) - 3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 20 DEG C, 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in HCl are stirred Base) -4,6- dimethyl pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea The solution of (40mg, 0.058mmol) in MeOH (10mL, 175mmol).After lcms analysis shows that initial substance disappears. Solvent is removed under vacuo.Residue is purified by preparing HPLC, the 1- (2- (5- ethyoxyl -6- oxygen in yellow solid is obtained Generation -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (three Methyl fluoride) phenyl) urea tri hydrochloride (7.79mg, 10.92 μm of ol, yield 18.94%)：1H NMR(400MHz,CD3OD)δ8.19 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=2.0Hz, 1H), 7.81-7.77 (m, 2H), 4.19-4.13 (m, 4H), 3.68- 3.47 (m, 8H), 2.95 (m, 2H), 2.55 (s, 6H), 1.49 (t, J=7.2Hz, 3H), 1.36 (d, J=7.2Hz, 3H)；ES- LCMS m/z 574.2(M+H)。
Embodiment 34：1- (4- (4- ethyoxyl -2- oxo -1,2- dihydro-pyrimidin -5- bases) -2- fluorophenyls) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The chloro- 4- ethoxies yl pyrimidines of the bromo- 2- of 5-
The sodium (0.202g, 8.78mmol) of fresh cut is added in EtOH (50mL).At 25 DEG C, obtained mixing is stirred Thing.After sodium disappearance, bromo- 2, the 4- dichloro pyrimidines (2g, 8.78mmol) of 5- are added into the mixture.At 25 DEG C, stirring Obtained mixture is stayed overnight.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo, obtains white solid The chloro- 4- ethoxies yl pyrimidines of the bromo- 2- of 5- (2g, 6.22mmol, yield 70.9%)：1H NMR(400MHz,CD3OD)δ8.51(s, 1H), 4.54-4.49 (m, 2H), 1.42 (t, J=7.0Hz, 3H)；ES-LCMS m/z 236.9,238.9(M+H).
Step 2：The bromo- 4- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyrimidine
NaH is added into solution of (4- methoxyphenyls) methanol (0.640g, 4.63mmol) in DMF (30mL) (0.202g,5.05mmol).At room temperature, obtained mixture is stirred.After 30 minutes, the chloro- 4- ethoxies of the bromo- 2- of 5- are added Yl pyrimidines (1g, 4.21mmol).At 90 DEG C, stir obtained mixture and stay overnight.Show that initial substance disappears in lcms analysis Afterwards.Solvent is removed under vacuo.Residue is dissolved in DCM (60mL), and uses H2O (20mL) and salt solution (20mL) washing. Through Na2SO4Organic layer is dried, filters and concentrates.By silica gel chromatography residue, the bromo- 4- ethyoxyls -2- of 5- are obtained ((4- methoxy-benzyls) epoxide) pyrimidine (180mg, 0.425mmol, yield 10.08%)：1H NMR(400MHz,CD3OD)δ 8.36 (s, 1H), 7.39 (d, J=8.8Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 5.34 (s, 2H), 4.55-4.50 (m, 2H), 3.81 (s, 3H), 1.43 (t, J=7.2Hz, 3H)；ES-LCMS m/z 338.9,340.9(M+H).
Step 3：1- (4- (4- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyrimidine -5- bases) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
On microwave, at 110 DEG C, 5- bromo- 4- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyrimidine is stirred (100mg, 0.295mmol), (the fluoro- 4- of 3- (3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene Base) urea groups) phenyl) boric acid (126mg, 0.295mmol), PdCl2(dppf) (21.57mg, 0.029mmol) and Cs2CO3 The solution of (192mg, 0.590mmol) in 1,4- dioxanes (9ml) and water (3ml) 15 minutes.Show and originate in lcms analysis After material disappears.Solvent is removed under vacuo.Residue is dissolved in DCM (60mL), and uses H2O (20mL) and salt solution (20mL) is washed.Through Na2SO4Organic layer is dried, filters and concentrates.Residue is purified by preparing TLC (PE/EA=2/1), is obtained To 1- (4- (4- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyrimidine -5- bases) -2- fluorophenyls) -3- (4- ((3- of grease Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (70mg, 0.086mmol, yield 29.2%)：1H NMR(400MHz,CD3OD)δ8.29(s,1H),8.13(s,1H),7.78(s,1H),7.54(m,1H),7.40-7.31(m, 4H),6.92(m,2H),6.62(m,1H),5.38(s,2H),4.89(m,2H),4.63-4.53(m,4H),3.79(s,3H), 1.72(s,3H),1.39(m,3H)；ES-LCMS m/z 643.1(M+H).
Step 4：1- (4- (4- ethyoxyl -2- oxo -1,2- dihydro-pyrimidin -5- bases) -2- fluorophenyls) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (4- (4- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyrimidine -5- in TFA are stirred Base) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (40mg, 0.062mmol) the solution in DCM (5mL, 7.44mmol).After lcms analysis shows that initial substance disappears.Use K2CO3Water Solution adjusts the mixture to pH 8.Solvent is removed under vacuo.Residue is dissolved in MeOH and filtered.It is prepared by filtrate HPLC purifying with obtain the 1- (4- (4- ethyoxyl -2- oxo -1,2- dihydro-pyrimidin -5- bases) -2- fluorophenyls) of white solid - 3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (18mg, 0.034mmol, yield 55.3%)：1H NMR(400MHz,CD3OD) δ 8.12 (t, J=8.4Hz, 1H), 7.82-7.79 (m, 2H), 7.58-7.55 (m, 1H), 7.33 (dd, J=12.4,2.0Hz, 1H), 7.27-7.24 (m, 1H), 6.64 (d, J=8.8Hz, 1H), 4.93-4.91 (m, 2H), 4.65 (d, J=7.6Hz, 2H), 4.52-4.47 (m, 2H), 1.75 (s, 3H), 1.39 (t, J=7.2Hz, 3H)；ES- LCMS m/z 523.2(M+H)。
Embodiment 35：1- (4- (2- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 6- chloro-2-ethoxies pyridines of 3-
The sodium (0.101g, 4.41mmol) of fresh cut is added in EtOH (50mL).At room temperature, obtained mixing is stirred Thing.After solid dissolving, bromo- 2, the 6- dichloropyridines (1g, 4.41mmol) of 3- are added.At 70 DEG C, obtained mixing is stirred Thing is stayed overnight.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Residue is dissolved in DCM (60mL) In, and use H2O (20mL) and salt solution (20mL) washing.Through Na2SO4Organic layer is dried, filters and concentrates.Pass through silica gel column chromatography (PE/EA=20 20/1) purify residue, obtain the chloro- 6- ethoxy pyridines of the bromo- 2- of 3-, bromo- 2, the 6- diethoxies pyridines of 3- and The white solid mixture (930mg, 3.85mmol, yield 87%) of the bromo- 6- chloro-2-ethoxies pyridines of 3-：1H NMR (400MHz,CD3OD) δ 7.85 (d, J=1.2Hz, 1H), 6.88 (d, J=8.0Hz, 1H), 4.42-4.36 (m, 2H), 1.39 (t, J=7.2Hz, 3H)；ES-LCMS m/z 235.9,237.9(M+H).
Step 2：The bromo- 2- ethyoxyls -6- of 3- ((4- methoxy-benzyls) epoxide) pyridine
At 0 DEG C, add into solution of (4- methoxyphenyls) methanol (257mg, 1.861mmol) in DMF (20mL) Enter NaH (135mg, 3.38mmol).At room temperature, obtained mixture is stirred.After 0.5h, the bromo- 6- of 3- are added chloro- 2- ethoxy pyridines (400mg, 1.691mmol).At 80 DEG C, stir obtained mixture and stay overnight.Shown in lcms analysis After beginning material disappears.Solvent is removed under vacuo.Residue is dissolved in DCM (60mL), and uses H2O (20mL) and salt solution (20mL) is washed.Through Na2SO4Organic layer is dried, filters and concentrates.Residue is purified by silica gel column chromatography and chirality HPLC, obtained To the bromo- 2- ethyoxyls -6- of 3- ((4- methoxy-benzyls) epoxide) pyridine (100mg, 0.296mmol, yield of white solid 17.48%)：1H NMR(400MHz,CDCl3) δ 7.61 (d, J=8.4Hz, 1H), 7.33 (d, J=8.8Hz, 2H), 6.88 (dd, J=6.8,2.0Hz, 2H), 6.23 (d, J=8.0Hz, 1H), 5.24 (s, 2H), 4.44-4.39 (m, 2H), 3.79 (s, 3H), 1.41 (t, J=7.0Hz, 3H)；ES-LCMS m/z 338.0,340.0(M+H).
Step 3：1- (4- (2- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
On microwave, at 110 DEG C, stirring 3- bromo- 2- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine (30mg, 0.089mmol), (the fluoro- 4- of 3- (3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea groups) Phenyl) boric acid (45.6mg, 0.106mmol), PdCl2(dppf)-DCM adducts (7.24mg, 8.87 μm of ol) and Cs2CO3 The solution of (57.8mg, 0.177mmol) in 1,4- dioxanes (3mL) and water (1mL) 15 minutes.Show and originate in lcms analysis After material disappears.The mixture is extracted with EA (20mL), and uses H2O (10mL) and salt solution (10mL) washing.By organic layer Through Na2SO4It is dried, filtered and concentrated.Residue is purified by preparing TLC (PE/EA=3/1), the 1- (4- of white solid are obtained (2- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea (30mg, 0.044mmol, yield 49.5%)：1H NMR(400MHz,CD3OD) δ 8.03 (t, J=8.6Hz, 1H), 7.77 (d, J=2.4Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.55-7.52 (m, 1H), 7.39-7.33 (m, 3H), 7.29 (d, J=8.8Hz, 1H), 6.91-6.89 (m, 2H), 6.61 (d, J=8.8Hz, 1H), 6.41 (d, J=8.0Hz, 1H), 5.31 (s, 2H), 4.89-4.88 (m, 2H), 4.62 (d, J=7.2Hz, 2H), 4.44-4.39 (m, 2H), 3.78 (s, 3H), 1.72 (s, 3H), 1.35 (t, J=7.0Hz, 3H)；ES-LCMS m/z 642.2(M+H).
Step 4：1- (4- (2- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (4- (2- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in TFA are stirred Base) -2- fluorophenyls) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (30mg, 0.047mmol) the solution in DCM (5mL, 3.72mmol).After lcms analysis shows that initial substance disappears, Na is used2CO3 The aqueous solution adjusts the mixture to pH 7.Solvent is removed under vacuo.Residue is dissolved in MeOH (5mL), filtered, and pass through HPLC purifying is prepared, 1- (4- (2- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorobenzene of white solid is obtained Base) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (3mg, 5.70 μm of ol, yield 12.20%)：1H NMR(400MHz,CD3OD) δ 8.02 (t, J=8.6Hz, 1H), 7.77 (d, J=2.8Hz, 1H), 7.59 (d, J =8.4Hz, 1H), 7.54 (dd, J=8.8,2.8Hz, 1H), 7.36 (dd, J=12.8,2.0Hz, 1H), 7.27 (d, J= 8.4Hz, 1H), 6.61 (d, J=9.2Hz, 1H), 6.26 (d, J=8.4Hz, 1H), 4.90-4.88 (m, 2H), 4.62 (d, J= 7.2Hz, 2H), 4.38-4.33 (m, 2H), 1.72 (s, 3H), 1.34 (t, J=7.2Hz, 3H)；ES-LCMS m/z 522.0(M+ H)。
Embodiment 36：1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 5-) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 3- fluorine pyridine -2- alcohol of 5-
At 80 DEG C, stirring the fluoro- 2- methoxypyridines (300mg, 1.456mmol) of the bromo- 3- of 5- the HBr aqueous solution (5mL, 48%) solution in.After TLC analyses (DCM/MeOH=10/1) show that initial substance disappears.Solvent is removed under vacuo, Obtain the bromo- 3- fluorine pyridine -2- alcohol of 5- (0.2g, 1.042mmol, yield 71.5%) of white-yellowish solid：1H NMR(400MHz, CD3OD) δ 7.57 (dd, J=10.0,2.4Hz, 1H), 7.46 (d, J=2.4,1.6Hz, 1H)；ES-LCMS m/z 192.0； 193.9(M+H)。
Step 2：1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 5-) phenyl) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
On microwave, at 110 DEG C, 1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyls -1,3,2- dioxaborolans are stirred Alkane -2- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (300mg, 0.588mmol), the bromo- 3- fluorine pyridine -2- alcohol (135mg, 0.705mmol) of 5-, PdCl2(dppf)-DCM adducts (48.0mg, 0.059mmol) and Cs2CO3The solution of (575mg, 1.764mmol) in 1,4- dioxanes (6mL) and water (2mL) 15 minutes. After lcms analysis shows that initial substance disappears.The mixture is dissolved in H2In O (20mL), and extracted with EA (30mL).To have Machine layer is through Na2SO4Dry, and concentrate.Purified, obtained by preparing TLC (DCM/MeOH=10/1) and preparing HPLC (neutrallty condition) To 1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 5-) phenyl) -3- (4- ((3- methyl oxa-s of white solid Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (8mg, 0.016mmol, yield 2.75%)：1H NMR (400MHz,CD3OD) δ 8.18 (t, J=8.4Hz, 1H), 7.84-7.80 (m, 2H), 7.58-7.55 (m, 2H), 7.43-7.39 (m, 1H), 7.36-7.34 (m, 1H), 6.65 (d, J=9.2Hz, 1H), 4.93-4.88 (m, 2H), 4.66 (d, J=7.2Hz, 1H),1.75(s,3H)；ES-LCMS m/z 496.0(M+H).
Embodiment 37：1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 4-) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：(4- fluorine pyridine -2- bases) t-butyl carbamate
At 80 DEG C, in N2Under, stir dicyclohexyl (2', 4', 6'- triisopropyl-[1,1'- diphenyl] -2- bases) phosphine The chloro- 4- fluorine pyridine (1g, 7.60mmol) of (0.072g, 0.152mmol), 2-, carbamate (4.45g, 38.0mmol)、Pd2(dba)3(0.070g, 0.076mmol) and Cs2CO3(12.39g, 38.0mmol) is in THF (80mL) Solutions overnight.After lcms analysis shows that initial substance disappears.By mixture H2O (100mL) is washed, and uses EA (100mL) is extracted.Organic layer is dried and concentrated, purified by column chromatography, (the 4- fluorine pyridines -2- in light yellow solid is obtained Base) t-butyl carbamate (1.3g, 5.55mmol, yield 73.1%)：1H NMR(400MHz,CD3OD)δ8.20-8.16(m, 1H), 7.65 (dd, J=12.0,2.4Hz, 1H), 6.81-6.77 (m, 1H), 1.52 (s, 9H)；ES-LCMS m/z 213.1(M+ H)。
Step 2：4- fluorine pyridine -2- amine
At 25 DEG C, (the 4- fluorine pyridine -2- bases) t-butyl carbamate (0.7g, 3.30mmol) stirred in HCl exists Solution in MeOH (50mL, 200mmol).After TLC analyses show that initial substance disappears.Solvent is removed under vacuo, is obtained To the 4- fluorine pyridine -2- amine hydrochlorates (0.5g, 3.20mmol, yield 97%) of solid：1H NMR(400MHz,CD3OD)δ7.96 (t, J=6.6Hz, 1H), 6.83-6.78 (m, 1H), 6.74-6.71 (m, 1H)；ES-LCMS m/z 134.9(M+Na).
Step 3：The bromo- 4- fluorine pyridine -2- amine of 5-
Et is added into suspension of the 4- fluorine pyridine -2- amine (0.6g, 4.04mmol) in MeCN (20mL)3N (0.563mL,4.04mmol).The solid all dissolves.Then, NBS (0.719g, 4.04mmol) is added.At 25 DEG C, stirring Obtained mixture is stayed overnight.Lcms analysis shows only 50% product.Add NBS (0.719g, 4.04mmol).At 25 DEG C, Obtained mixture is stirred to stay overnight.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By residue It is dissolved in DCM (100mL), and uses H2O (50mL) and salt solution (50mL) washing.By organic layer through Na2SO4Dry, filter and dense Contracting.By prepare TLC (PE/EA=3/1) purify residue, obtain white-yellowish solid the bromo- 4- fluorine pyridine -2- amine of 5- (0.3g, 1.319mmol, yield 32.7%)：1H NMR(400MHz,CDCl3) δ 8.11 (d, J=9.6Hz, 1H), 6.26 (d, J= 10.0Hz,1H),4.55(brs,2H)；ES-LCMS m/z 192.9(M+H).
Step 4：The bromo- 4- fluorine pyridine -2- alcohol of 5-
By the bromo- 4- fluorine pyridine -2- amine (100mg, 0.524mmol) of 5- and 50%H3PO2The aqueous solution (691mg, 5.24mmol) With water (3mL) mixing.The mixture is cooled to about 2 DEG C, and adds NaNO2 (43.3mg, 0.628mmol) in water (1mL) Solution, while strong stirring with keeping temperature be less than 5 DEG C.At a lower temperature, the mixture is stirred 30 minutes, then in room It is stirred under temperature 12 hours.After lcms analysis shows that initial substance disappears.By the filtering of obtained sediment, and it is washed with water Wash.By filtration cakes torrefaction and concentrate, obtain 5- bromo- 4- fluorine pyridine -2- alcohol (80mg, the 0.417mmol, yield of yellow oil 80%)：1H NMR(400MHz,CD3OD) δ 7.77 (d, J=8.8Hz, 1H), 6.31 (d, J=10.8Hz, 1H)；ES-LCMS m/ z 191.9,193.9(M+H)。
Step 5：1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 4-) phenyl) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
At 110 DEG C, the bromo- 4- fluorine pyridine -2- alcohol (40mg, 0.208mmol) of stirring 5-, (the fluoro- 4- of 3- (3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea groups) phenyl) boric acid (107mg, 0.250mmol), Cs2CO3(136mg, 0.417mmol) and PdCl2(dppf) (15.24mg, 0.021mmol) is in 1,4- dioxanes (3mL) and water Solution in (1mL) 15 minutes.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By residue It is dissolved in EA (20mL), and uses H2O (10mL) and salt solution (10mL) washing.By organic layer through Na2SO4It is dried, filtered and concentrated. Residue is purified by preparing TLC (DCM/MeOH=10/1), 1- (the fluoro- 4- of 2- (fluoro- 6- oxos -1, the 6- dihydro pyrroles of 4- are obtained Pyridine -3- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (2.88mg, 5.81 μm of ol, yield 2.79%)：1H NMR(400MHz,CD3OD) δ 8.17 (t, J=8.4Hz, 1H), 7.78 (d, J=2.4Hz, 1H), 7.64 (d, J=9.6Hz, 1H), 7.55-7.52 (m, 1H), 7.30-7.21 (m, 2H), 6.62 (d, J=8.8Hz, 1H), 6.30 (d, J=12.8Hz, 1H), 4.89 (d, J=6.4Hz, 2H), 4.62 (d, J=7.6Hz, 2H), 1.72 (s, 3H)；ES- LCMS m/z 496.1(M+H)。
Embodiment 38：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea
Step 1：1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (3- (trifluoromethyl) phenyl) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (100mg, 0.253mmol) and Et3N (0.053mL, 0.379mmol) adds DPPA in the solution in 1,4- dioxanes (5mL) (84mg,0.303mmol).After 10 min, 3- (trifluoromethyl) aniline (61.1mg, 0.379mmol) is added.At 60 DEG C Under, stir obtained mixture and stay overnight.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Pass through TLC (DCM/MeOH=20/1) purifying residues are prepared, 1- (2- (4- ethyoxyls -6- ((the 4- methoxybenzyls of white solid are obtained Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea (10mg, 0.018mmol, production Rate 7.14%)：1H NMR(400MHz,CD3OD)δ1H NMR(400MHz,CD3OD)δ9.21(s,1H),8.27(s,1H),7.93 (br.s., 1H), 7.63 (m, 1H), 7.49 (t, J=8.0Hz, 1H), 7.38 (d, J=8.8Hz, 2H), 7.32 (d, J= 8.4Hz, 1H), 6.91 (d, J=8.8Hz, 2H), 6.48 (s, 1H), 5.31 (s, 2H), 4.14 (m, 2H), 3.79 (s, 3H), (2.58 s, 3H), 1.35 (t, J=7.0Hz, 3H)；ES-LCMS m/z 554.1(M+H).
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea
At 25 DEG C, (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl is phonetic by 1- of the stirring in HCl Pyridine -5- bases) -3- (3- (trifluoromethyl) phenyl) solution of urea (10mg, 0.018mmol) in MeOH (2mL, 8.00mmol). After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By preparing HPLC (instruments: DB/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs：MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：30- 60 (B%)) purifying residue.After freeze, 1- (2- (4- ethyoxyl -6- oxos -1,6- bis- of yellow solid are obtained Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea hydrochlorides (3mg, 6.23 μm of ol, yield 34.5%)：1H NMR(400MHz,CD3OD) δ 9.52 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.63 (d, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.36 (d, J=7.6Hz, 1H), 6.14 (s, 1H), 4.34 (m, 2H), 2.75 (s, 3H), 1.47 (t, J=6.8Hz, 3H)；ES-LCMS m/z 434.1(M+H).
Embodiment 39：1- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) -3- (4- methyl -2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) pyrimidine -5- bases) urea
Step1：1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea
Triphosgene is added into solution of the chloro- 4- methylpyrimidines -5- amine (65mg, 0.453mmol) of 2- in THF (5mL) (53.7mg,0.181mmol).At 50 DEG C, obtained mixture is stirred.After 30 minutes, lcms analysis shows starting material Matter disappears.Solvent is removed under vacuo, obtains 2- chloro- 5- isocyanatos -4- methylpyrimidines (70mg, 0.397mmol, yield 88%).To 1- (5- amino -3- (trifluoromethyl) pyridine -2- bases) ethyl ketones (75mg, 0.367mmol) and Et3N(0.154mL, 1.102mmol) added in the solution in THF (5mL) 2- chloro- 5- isocyanatos -4- methylpyrimidines (68.5mg, 0.404mmol) the solution in THF (5mL).At 50 DEG C, obtained mixture is stirred.Initial substance is shown in lcms analysis After disappearance.Solvent is removed under vacuo.Residue is dissolved in EA, and uses H2O is washed.Organic layer is dried and concentrated, led to Preparation TLC (DCM/MeOH=20/1) purifying is crossed, 1- (6- acetyl group -5- (trifluoromethyl) pyridines -3- of yellow solid are obtained Base) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea (50mg, 0.134mmol, yield 36.4%)：1H NMR(400MHz,CD3OD) δ 9.03 (s, 1H), 8.83 (d, J=2.4Hz, 1H), 8.52 (s, 1H), 2.64 (s, 3H), 2.52 (s, 3H)；ES-LCMS m/z 374.0(M+H)。
Step 2：1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (7- (benzyloxy) furans simultaneously [2,3- C] pyridin-4-yl) -4- methylpyrimidine -5- bases) urea
On microwave, at 110 DEG C, 7- (benzyloxy) -4- (4,4,5,5- tetramethyls-DOX -2- are stirred Base) furans simultaneously [2,3-c] pyridine (56.4mg, 0.161mmol), 1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea (60mg, 0.161mmol), PdCl2(dppf) (11.75mg, 0.016mmol) and Cs2CO3The solution of (105mg, 0.321mmol) in 1,4- dioxanes (9mL) and water (3mL) 15 minutes.Shown in lcms analysis After initial substance disappears.Solvent is removed under vacuo.Residue is dissolved in EA (30mL), and uses H2O (10mL) and salt solution (10mL) is washed.By organic layer through Na2SO4It is dried, filtered and concentrated.Residue is purified by preparing TLC (PE/EA=1/1), Obtain 1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3- (2- (7- (benzyloxy) furans simultaneously [2,3- of brown solid C] pyridin-4-yl) -4- methylpyrimidine -5- bases) urea (60mg, 0.107mmol, yield 66.4%)：1H NMR(400MHz, CD3OD) δ 9.18 (s, 1H), 8.97-8.92 (m, 2H), 8.56 (d, J=8.0Hz, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.56 (d, J=7.6Hz, 2H), 7.42-7.35 (m, 3H), 5.66 (s, 2H), 2.68 (s, 3H), 2.18 (s, 3H)；ES-LCMS m/z 563.0(M+H)。
Step 3：1- (2- (7- (benzyloxy) furans simultaneously [2,3-c] pyridin-4-yl) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea
At 20 DEG C, to 1- (6- acetyl group -5- (trifluoromethyl) pyridin-3-yl) -3-, ((7- (benzyloxy) furans is simultaneously by 2- [2,3-c] pyridin-4-yl) -4- methylpyrimidine -5- bases) add in solution of the urea (60mg, 0.107mmol) in THF (5mL) Methyl-magnesium-chloride (0.356mL, 1.067mmol).After lcms analysis shows that initial substance disappears.With the NH of saturation4Cl quenches Go out the mixture.Filter the mixture.Filtrate is concentrated, by preparing TLC (DCM/MeOH=20/1) purifying, 1- (2- (7- are obtained (benzyloxy) furans simultaneously [2,3-c] pyridin-4-yl) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (three Methyl fluoride) pyridin-3-yl) urea (30mg, 0.051mmol, yield 47.8%)：1H NMR(400MHz,CD3OD)δ9.15(s, 1H), 8.92 (s, 1H), 8.76 (d, J=2.0Hz, 1H), 8.41 (d, J=2.4Hz, 1H), 7.99 (s, 1H), 7.78 (d, J= 2.0Hz, 1H), 7.53 (d, J=7.2Hz, 2H), 7.38-7.29 (m, 3H), 5.62 (s, 2H), 2.63 (s, 3H), 1.60 (s, 6H)；ES-LCMS m/z 579.1(M+H).
Step 4：1- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) -3- (4- methyl -2- (7- oxygen Generation -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) pyrimidine -5- bases) urea
At 20 DEG C, in H2Under atmosphere, stirring 1- (2- (7- (benzyloxy) furans simultaneously [2,3-c] pyridin-4-yl) -4- first Yl pyrimidines -5- bases) -3- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea (15mg, 0.026mmol) With solution of the Pd/C (10mg, 10%) in MeOH (5mL).After 0.5h, TLC analyzes (DCM/MeOH=20/1) and shown After showing that initial substance disappears.Filter the mixture.Filtrate is concentrated, by preparing HPLC (in neutral conditions) purifying, is obtained White solid 1- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) -3- (4- methyl -2- (7- oxos - 6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) pyrimidine -5- bases) urea (3.29mg, 6.74 μm of ol, yield 26.0%).1H NMR(400MHz,CD3OD)δ9.08(s,1H),8.77(br.s.,1H),8.41(br.s.,1H),8.34(s,1H),8.06(s, 1H),7.82(s,1H),2.61(s,3H),1.61(s,6H)；ES-LCMS m/z 489.1(M+H).
Embodiment 40：1- (the fluoro- 4- of 2- (2- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
On microwave, at 110 DEG C, the bromo- 6- picolines -2- alcohol (17.69mg, 0.094mmol) of stirring 5-, 1- (2- Fluoro- 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (40mg, 0.078mmol), PdCl2(dppf)(5.74mg,7.84μ ) and Cs mol2CO3The solution of (51.1mg, 0.157mmol) in 1,4- dioxanes (1.5mL) and water (0.5mL) 15 minutes. After lcms analysis shows that initial substance disappears.The mixture is dissolved in EA (20mL), and uses H2O (10mL) is washed.It will close And organic extract washed with salt solution (10mL), through Na2SO4It is dried, filtered and concentrated.Residue is purified by preparing HPLC. After freeze, 1- (the fluoro- 4- of 2- (2- methyl -6- oxo -1,6- dihydropyridine -3- bases) benzene of white solid is obtained Base) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (10.21mg, 0.020mmol, Yield 26.1%)：1H NMR(400MHz,CD3OD) δ 8.13 (t, J=8.6Hz, 1H), 7.78 (d, J=2.4Hz, 1H), 7.55- 7.50 (m, 2H), 7.14-7.06 (m, 2H), 6.62 (d, J=8.8Hz, 1H), 6.42 (d, J=9.2Hz, 1H), 4.89-4.88 (m, 2H), 4.62 (d, J=7.2Hz, 2H), 2.28 (s, 3H), 1.72 (s, 3H)；ES-LCMS m/z 492.1(M+H).
Embodiment 41：1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
Step 1：3- (4- (3- (the bromo- 3- methylpyrazines -2- bases of 5-) urea groups) -2- (trifluoromethyl) phenyl) -2,2- diformazans Base ethyl propionate
Three light are added into solution of the bromo- 3- methylpyrazines -2- amine (200mg, 1.064mmol) of 5- in THF (30mL) Gas (110mg, 0.372mmol).At 70 DEG C, obtained mixture is stirred.After lcms analysis shows that initial substance disappears. Solvent is removed under vacuo, obtains the bromo- 2- isocyanatos -3- methylpyrazines of 5- (220mg, 0.977mmol, yield 92%).To 3- (4- amino -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (270mg, 0.934mmol) are in THF (20mL) Solution in add NaH (112mg, 2.80mmol).At room temperature, obtained mixture is stirred.After 30 minutes, 5- is added Solution of the bromo- 2- isocyanatos -3- methylpyrazines (200mg, 0.934mmol) in THF (20mL).At 70 DEG C, stir The mixture arrived.After 2 hr, lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Residue is dissolved in In EA (60mL), and use H2O (20mL) and salt solution (20mL) washing.By organic layer through Na2SO4It is dried, filtered and concentrated.Pass through Silica gel column chromatography (PE/EA=3/1) purifies residue, obtains the 3- (4- (3- (the bromo- 3- methylpyrazines -2- bases of 5-) of white solid Urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (330mg, 0.357mmol, yield 38.2%)：1H NMR (400MHz,CD3OD) δ 8.33 (s, 1H), 7.98 (s, 1H), 7.63 (d, J=7.2Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 4.18-4.13 (m, 2H), 3.08 (d, J=8.0Hz, 2H), 2.54 (s, 3H), 1.26-1.22 (m, 3H), 1.16 (s, 6H)；ES- LCMS m/z 503.0,505.0(M+H)。
Step 2：3- (4- (3- (5- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- methyl pyrroles Piperazine -2- bases) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls
On microwave, at 110 DEG C, 3- (4- (3- (the bromo- 3- methylpyrazines -2- bases of 5-) urea groups) -2- (fluoroforms are stirred Base) phenyl) -2,2- ethyl dimethyls (240mg, 0.477mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) - 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (184mg, 0.477mmol), PdCl2 (dppf) (34.9mg, 0.048mmol) and Cs2CO3(311mg, 0.954mmol) is in 1,4- dioxanes (9mL) and water (3mL) Solution 15 minutes.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Residue is dissolved in EA In (60mL), and use H2O (20mL) and salt solution (20mL) washing.By organic layer through Na2SO4It is dried, filtered and concentrated.Pass through system Standby TLC (DCM/MeOH=40/1) purifies residue, obtains 3- (4- (3- (5- (5- ethyoxyls -6- ((the 4- methoxies of yellow solid Base benzyl) epoxide) pyridin-3-yl) -3- methylpyrazine -2- bases) urea groups) -2- (trifluoromethyl) phenyl) -2,2- neopentanoic acids Ethyl ester (160mg, 0.192mmol, yield 40.2%)：1H NMR(400MHz,CD3OD)8.69(br.s.,1H),8.34 (br.s., 1H), 7.82 (d, J=2.0Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.40 (d, J=8.4Hz, 1H), 7.21 (d, J=8.4Hz, 2H), 6.91 (d, J=8.8Hz, 1H), 5.39 (s, 2H), 4.18-4.14 (m, 4H), 3.78 (s, 3H), 3.07 (s, 3H), 2.56 (s, 2H), 1.24 (t, J=7.0Hz, 6H), 1.16 (s, 6H)；ES-LCMS m/z 682.2(M+H).
Step 3：1- (5- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- methylpyrazines -2- Base) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
At 0 DEG C, to 3- (4- (3- (5- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- first Base pyrazine -2- bases) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (80mg, 0.117mmol) are in THF LAH (8.91mg, 0.235mmol) is added in solution in (10mL).At room temperature, the mixture that stirring is obtained is stayed overnight. After lcms analysis shows that initial substance disappears.Use H2The mixture is quenched in O and NaOH (10%).Solvent is removed under vacuo. Residue is dissolved in DCM (40mL), and uses H2O (20mL) and salt solution (20mL) washing.Through Na2SO4Dry organic layer, filtering And concentrate.Residue is purified by preparing TLC (DCM/MeOH=40/1), mixture 1- (5- (the 5- second of light yellow solid is obtained Epoxide -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyl -2,2- diformazans Base propyl group) -3- (trifluoromethyl) phenyl) urea (40mg, 0.054mmol, yield 46.3%)：1H NMR(400MHz,CD3OD) 8.63 (s, 1H), 8.29 (d, J=1.6Hz, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=6.0Hz, 1H), 7.43-7.38 (m, 3H), 6.89 (d, J=8.8Hz, 2H), 5.38 (s, 2H), 4.20-4.14 (m, 2H), 3.78 (s, 3H), 3.42-3.33 (m, 2H), 2.78 (s, 2H), 2.64 (s, 3H), 1.44 (t, J=7.0Hz, 3H), 0.84 (s, 6H)；ES-LCMS m/z 640.2(M+H)。
Step 4：1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
At 20 DEG C, 1- (5- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in HCl are stirred Base) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea (40mg, 0.063mmol) the solution in MeOH (10mL, 175mmol).After lcms analysis shows that initial substance disappears.In vacuum Lower removing solvent.Residue is purified by preparing HPLC, 1- (5- (5- ethyoxyl -6- oxos -1,6- in yellow solid are obtained Dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) benzene Base) urea hydrochloride (7.06mg, 0.013mmol, yield 20.31%)：1H NMR(400MHz,CD3OD and DMSO-d6)8.68 (s,1H),8.03(s,1H),7.82(s,1H),7.78(m,1H),7.63(s,1H),7.59(m,1H),4.20-4.14(m, 2H),3.50(s,2H),2.83(s,2H),2.09(s,3H),1.53(m,3H),0.89(s,6H)；ES-LCMS m/z 520.1 (M+H)。
Embodiment 42：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea
Step 1：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (3- (trifluoromethyl) phenyl) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (100mg, 0.253mmol) and Et3N (0.053mL, 0.379mmol) adds DPPA in the solution in 1,4- dioxanes (5ml) (84mg,0.303mmol).After 10 min, 3- (trifluoromethyl) aniline (61.1mg, 0.379mmol) is added.At 60 DEG C Under, stir obtained mixture and stay overnight.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Pass through TLC (DCM/MeOH=20/1) purifying residues are prepared, 1- (2- (5- ethyoxyls -6- ((the 4- methoxybenzyls of white solid are obtained Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea (60mg, 0.108mmol, production Rate 42.9%)：1H NMR(400MHz,CD3OD) δ 9.14 (s, 1H), 8.71 (d, J=2.0Hz, 1H), 8.12 (d, J=2.0Hz, 1H), 7.96 (br.s., 1H), 7.65 (d, J=8.0Hz, 1H), 7.51 (m, 1H), 7.44 (d, J=8.8Hz, 2H), 7.27 (m, 1H),6.94(m,2H),5.42(s,2H),4.21-4.16(m,2H),3.82(s,3H),2.61(s,3H),1.49-1.45(m, 3H)；ES-LCMS m/z 554.1(M+H).
Step 2：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in TFA are stirred Base) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) ureas (60mg, 0.108mmol) DCM (5mL, Solution in 37.2mmol).After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By preparing HPLC (instrument: DB/Column:ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys： The distribution description of 25mL/min/ gradients：38-68 (B%)) purifying residue.After freeze, the 1- of yellow solid is obtained (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) phenyl) Urea hydrochloride (17mg, 0.036mmol, yield 33.0%)：1H NMR(400MHz,CD3OD) δ 9.13 (s, 1H), 8.12 (d, J= 2.0Hz, 1H), 7.94 (s, 1H), 7.87 (d, J=2.0Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 7.49 (m, 1H), 7.32 (d, J=7.2Hz, 1H), 4.17 (m, 2H), 2.60 (s, 3H), 1.49 (t, J=7.2Hz, 3H)；ES-LCMS m/z 434.0(M +H)。
Embodiment 43：1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) oxygen Base) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (300mg, 0.759mmol) and Et3Added in solution of the N (0.159mL, 1.138mmol) in 1,4- dioxanes (10mL) DPPA (251mg, 0.910mmol).After 10 min, add 4- amino -2- (trifluoromethyl) benzonitrile (212mg, 1.138mmol).At 60 DEG C, stir obtained mixture and stay overnight.After lcms analysis shows that initial substance disappears.True Sky is lower to remove solvent.Purifying residue (is eluted) with DCM to DCM/MeOH=20/1 by column chromatography.TLC (DCM/ will be passed through MeOH=20/1, Rf=0.4) find that all fractions comprising product merge, and concentrate in a vacuum, and by preparing TLC (DCM/MeOH=20/1) repurity residue, obtains 1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- of brown solid (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (40mg, 0.069mmol, Yield 9.11%)：1H NMR(400MHz,CD3OD) δ 9.09 (s, 1H), 8.69 (d, J=2.0Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90-7.88 (m, 1H), 7.82-7.80 (m, 1H), 7.41 (d, J=8.4Hz, 2H), 6.91 (d, J= 8.8Hz, 2H), 5.39 (s, 2H), 4.19-4.15 (m, 2H), 3.79 (s, 3H), 2.58 (s, 3H), 1.44 (t, J=7.0Hz, 3H),LCMS m/z 579.1(M+H)。
Step 2：1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines - 3- yls) -4- methylpyrimidine -5- bases) urea
At 25 DEG C, 1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- in TFA are stirred ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (40mg, 0.069mmol) DCM (3mL, Solution in 2.232mmol).After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By preparing HPLC (instruments: DB/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/ The distribution description of min/ gradients：38-68 (B%)) purifying residue.After freeze, 1- (the 4- cyanogen of yellow solid is obtained Base -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) urea hydrochloride (18mg, 0.036mmol, yield 52.2%)：1H NMR(400MHz,DMSO-d6)δ11.91(br.s.,1H), 9.96 (s, 1H), 8.91 (s, 1H), 8.64 (s, 1H), 8.17 (s, 1H), 8.04 (d, J=8.4Hz, 1H), 7.91 (br.s., 1H), 7.80 (d, J=8.8Hz, 1H), 7.57 (s, 1H), 4.03-3.98 (m, 2H), 2.43 (br.s., 3H), 1.34 (t, J= 7.0Hz,3H)；ES-LCMS m/z 459.0(M+H).
Embodiment 44：1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) oxygen Base) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (200mg, 0.506mmol) and Et3Added in solution of the N (0.106mL, 0.759mmol) in 1,4- dioxanes (10mL) DPPA(167mg,0.607mmol).After 10 min, add 4- amino -2- (trifluoromethyl) benzonitrile (141mg, 0.759mmol).At 60 DEG C, stir obtained mixture and stay overnight.After lcms analysis shows that initial substance disappears.True Sky is lower to remove solvent.Residue is purified by preparing TLC (DCM/MeOH=20/1), the 1- (4- cyano group -3- of brown solid are obtained (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) urea (30mg, 0.052mmol, yield 10.25%)：1H NMR(400MHz,CD3OD)δ8.12-8.08(m,2H),7.39- 7.36(m,3H),6.92-6.86(m,4H),6.44(s,1H),5.28(s,2H),4.10-4.07(m,2H),3.78(s,3H), 2.40(s,3H),1.34-1.31(m,3H)；LCMS m/z 579.1(M+H).
Step 2：1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines - 3- yls) -4- methylpyrimidine -5- bases) urea
At 25 DEG C, 1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- in HCl are stirred ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (40mg, 0.069mmol) MeOH (2mL, Solution in 8.00mmol).After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By preparing HPLC purifies residue (instrument: DB/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ Flow velocity：The distribution description of 25mL/min/ gradients：28-58 (B%)).After freeze, 1- (the 4- cyanogen of yellow solid is obtained Base -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) urea hydrochloride (8mg, 0.016mmol, yield 23.38%).1H NMR(400MHz,CD3OD)δ9.43(s,1H),8.30(s, 1H), 8.21 (s, 1H), 7.92 (d, J=8.8Hz, 1H), 7.82 (d, J=10.4Hz, 1H), 6.14 (s, 1H), 4.31 (m, 2H), 2.72 (s, 3H), 1.46 (t, J=7.2Hz, 3H)；ES-LCMS m/z 459.1(M+H).
Embodiment 45：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ( Quinoline is for methyl) -3- (trifluoromethyl) phenyl) urea
Step 1：(4- amino -2- (trifluoromethyl) phenyl) (morpholinomethyl) ketone
At 25 DEG C, stirring 4- amino -2- (trifluoromethyl) benzoic acid (1g, 4.87mmol), morpholine (0.637g, 7.31mmol), EDC (1.402g, 7.31mmol), HOBt (1.120g, 7.31mmol) and DIEA (2.55mL, 14.62mmol) Solution in DCM (60mL).After 2 hr, lcms analysis shows that initial substance disappears.Solvent is removed under vacuo, and Residue is purified by column chromatography (DCM/MeOH=20/1), (4- amino -2- (trifluoromethyl) benzene of colorless oil is obtained Base) (morpholinomethyl) ketone (1.3g, 4.59mmol, yield 94%)：1H NMR(400MHz,CD3OD) δ 7.06 (d, J= 8.4Hz, 1H), 6.96 (d, J=2.0Hz, 1H), 6.87-6.85 (m, 1H), 3.74-3.66 (m, 6H), 3.58-3.53 (m, 2H)；ES-LCMS m/z 275.1(M+H).
Step 2：4- (morpholinomethyl) -3- (trifluoromethyl) aniline
To (4- amino -2- (trifluoromethyl) phenyl) (morpholino) ketone (0.8g, 2.92mmol) in THF (50mL) BH is added in solution3·THF(8.75mL,8.75mmol).At 70 DEG C, stir obtained mixture and stay overnight.In lcms analysis After showing that initial substance disappears.The mixture is quenched with MeOH, and is stirred overnight at 70 DEG C.Solvent is removed under vacuo, Obtain 4- (morpholinomethyl) -3- (trifluoromethyl) aniline (0.8g, 1.784mmol, yield 61.2%) of light yellow oil ：1H NMR(400MHz,CD3OD) δ 7.86 (d, J=8.4Hz, 1H), 7.46 (d, J=2.4Hz, 1H), 7.36 (d, J=8.0Hz, 1H),4.48(s,2H),4.04-4.01(m,2H),3.88-3.81(m,2H),3.45-3.40(m,2H),3.34-3.28(m, 2H)；ES-LCMS m/z 261.1(M+H).
Step 3：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (morpholinoes Methyl) -3- (trifluoromethyl) phenyl) urea
To 4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines (100mg, 0.271mmol) and Et3N (0.038mL, 0.271mmol) adds triphosgene in the solution in anhydrous THF (20mL) (28.2mg,0.095mmol).At 70 DEG C, in N2Under atmosphere, obtained mixture is stirred.After 30 minutes, TLC is analyzed (PE/EA=3/1) display initial substance disappears.Solvent is removed under vacuo, obtains 3- ethyoxyls -5- (the fluoro- 4- isocyanatos of 3- Phenyl) -2- ((4- methoxy-benzyls) epoxide) pyridine (100mg, 0.254mmol, yield 93%).In N2Under atmosphere, at 80 DEG C Under, to 4- (morpholinomethyl) -3- (trifluoromethyl) aniline (117mg, 0.394mmol) and Et3N(0.110mL, 3- ethyoxyls -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- first 0.789mmol) is added dropwise in the solution in THF (20mL) Oxy-benzyl) epoxide) solution of the pyridine (100mg, 0.263mmol) in THF (20mL).Starting material is shown in LC-MS analyses After matter disappears.Filter the mixture.Filtrate is concentrated, by preparing TLC (DCM/MeOH=15/1) and preparing HPLC purifying, is obtained To 1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (morpholinoes of pink solid Methyl) -3- (trifluoromethyl) phenyl) urea hydrochloride (23.07mg, 0.040mmol, yield 15.13%)：1H NMR(400MHz, CD3OD) δ 8.16 (t, J=8.4Hz, 1H), 8.08 (d, J=2.0Hz, 1H), 7.81 (dd, J=8.6,2.2Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.43 (dd, J=8.4,2.0Hz, 1H), 7.40-7.35 (m, 3H), 4.49 (s, 2H), 4.19-4.13 (m,2H),4.07-4.04(m,2H),3.84-3.78(m,2H),3.49-3.46(m,2H),3.36-3.33(m,2H),1.46 (t, J=7.0Hz, 3H)；ES-LCMS m/z 535.2(M+H).
Embodiment 46：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea (compound A)
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (100mg, 0.253mmol) in 1,4- dioxanes (30ml)3N (0.38.4mg, 0.379mmol) and DMAP (3.09mg, 0.025mmol), and at 25 DEG C, stir the mixture 15 minutes.Then, add DPPA (104mg, 0.379mmol), and the mixture is stirred 15 minutes.Add 5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine (49.1mg, 0.253mmol), and stir at 80 DEG C the mixture 3 hours.The mixture is concentrated, and by preparing TLC (DCM/MeOH=15:1,Rf=residue 0.5) is purified, obtain 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) Pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea (20mg), adds TFA (20mL, 10% in DCM), and stir at 25 DEG C the mixture 1 hour thereto.Concentrate the mixing Thing, and by preparing HPLC (instrument: Gilson GX 281；Post：Gemini150*25mm*5um；Mobile phase A: water (0.05% Ammonia spirit)；Mobile phase B: MeCN；Gradient: 36-66 (B%)；Flow velocity：25mL/min；Run time: 10min) purifying remnants Thing, obtains 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- of white solid (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea (1.83mg, 3.92 μm of ol, yield 1.551%)：1H NMR(400MHz,CD3OD) δ 9.18 (s, 1H), 7.78 (s, 1H), 6.74 (s, 1H), 5.99 (s, 1H), 4.11 (q, J= 6.8Hz, 2H), 2.56 (s, 3H), 1.58 (s, 6H), 1.36 (t, J=7.2Hz, 3H)；ES-LCMS(m/z):467.1(M+H).
Embodiment 47：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
Step1：1- (4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- dimethyl propyls) -3- (fluoroforms Base) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
At 20 DEG C, in N2Under, to 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5-carboxylic acid is (disposable in the solution in 0.2g, 0.506mmol) dioxanes (5mL) to add Et3N(0.106mL, 0.759mmol) with DPPA (0.167g, 0.607mmol).At room temperature, the reactant mixture is stirred 30 minutes.To the mixture Middle addition 4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- dimethyl propyls) -3- (trifluoromethyl) aniline The solution of (0.146g, 0.405mmol) in 1mL 1,4- dioxanes (1mL).The reaction solution is heated to 100 DEG C, simultaneously Stirring 3 hours.The solution is concentrated under vacuum, and by preparing TLC (DCM/MeOH=20:1,Rf=residue 0.5) is purified, Obtain 1- (4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- dimethyl propyls) -3- (trifluoros of light yellow solid Methyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (40mg, 0.053mmol, yield 10.5%)：1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.39(br.s.,1H), 7.57-7.55(m,1H),7.51(s,1H),7.44-7.40(m,1H),7.34-7.32(m,2H),6.85-6.82(m,2H), 6.24(s,1H),5.28(s,2H),4.04-4.01(m,2H),3.75(s,3H),3.21(s,2H),2.70(s,2H),2.48 (s, 3H), 1.31 (t, J=6.9Hz, 3H), 0.87 (s, 9H), 0.74 (s, 6H), 0.01 (s, 6H)；ES-LCMS m/z 754.3 (M+H)。
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N2Under, 1- (4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- diformazans of stirring Base propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- Methylpyrimidine -5- bases) HCl in MeOH is disposably added in solution of the urea (40mg, 0.053mmol) in DCM (3mL) (0.5mL,2.000mmol).At 20 DEG C, the reactant mixture is stirred 1 hour.Then, the solution is concentrated.By preparing HPLC (instrument: DC/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/min/ Gradient distribution description：12-42 (B%)) purifying residue, obtain 1- (2- (4- ethyoxyl -6- oxos -1,6- bis- of white solid Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) Urea hydrochloride (10.12mg, 0.018mmol, yield 34.2%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR (400MHz,CD3OD) δ 9.47 (s, 1H), 8.30 (s, 1H), 7.90 (d, J=2.2Hz, 1H), 7.59-7.57 (m, 1H), 7.45-7.43(m,1H),6.12(s,1H),4.33-4.28(m,2H),3.33-3.31(m,2H),2.78(s,2H),2.73(s, 3H), 1.46 (t, J=7.1Hz, 3H), 0.84 (s, 6H)；ES-LCMS m/z 520.1(M+H).
Embodiment 48：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
Step1：1- (4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- dimethyl propyls) -3- (fluoroforms Base) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N22- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- stirred under atmosphere Base) disposably add in the solution of -4- methylpyrimidine -5- carboxylic acids (0.1g, 0.253mmol) in 1,4- dioxanes (5mL) Et3N (0.053mL, 0.379mmol) and DPPA (0.084g, 0.303mmol).At room temperature, 30 points of stirring reaction mixture Clock.4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- dimethyl propyls) -3- (fluoroforms are added into the solution Base) solution of the aniline (0.091g, 0.253mmol) in 1mL 1,4- dioxanes.Reaction solution is heated to 100 DEG C and stirred Mix, continue 3 hours.Then, the solution is concentrated under vacuum, and by preparing TLC (DCM/MeOH=20:1,Rf=0.6) pure Change residue, obtain 1- (4- (3- ((t-butyldimethylsilyl) epoxide) -2,2- dimethyl propylenes of light yellow solid Base) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5- bases) urea (80mg, 0.106mmol, yield 42.0%)：1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.71 (s, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 7.38 (d, J=7.3Hz, 2H), 6.88 (br.s., 1H), 6.80 (d, J= 7.3Hz,1H),6.44(br.s.,1H),5.42(s,2H),4.13-4.10(m,2H),3.72(s,3H),3.21(s,2H), 2.70 (s, 2H), 2.43 (s, 3H), 1.40 (t, J=6.7Hz, 3H), 0.86 (s, 9H), 0.74 (s, 6H), 0.00 (s, 6H).
Step 2：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N21- (4- (the 3- ((t-butyldimethylsilyl) epoxide) -2,2- stirred under atmosphere Dimethyl propyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea (80mg, 0.106mmol) disposably added in MeOH in the solution in DCM (2mL) In HCl (0.5mL, 2.000mmol).At 20 DEG C, stirring reaction mixture 1 hour.Then, concentrate solution.By preparing HPLC purifies residue (post: ASB C18 150*25mm；Mobile phase A: water+0.1%HCl；Mobile phase B: MeCN；Flow velocity： 25mL/min；Gradient distribution description：34-64 (B%)), obtain 1- (2- (5- ethyoxyl -6- oxos -1,6- bis- of yellow solid Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) Urea hydrochloride (29.96mg, 0.052mmol, yield 49.3%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR (400MHz,CD3OD) δ 9.10 (s, 1H), 8.10 (s, 1H), 7.88-7.82 (m, 2H), 7.58 (d, J=8.8Hz, 1H), 7.42 (d, J=8.6Hz, 1H), 4.16-4.13 (m, 2H), 3.33-3.31 (m, 2H), 2.77 (s, 2H), 2.58 (s, 3H), 1.48 (t, J=7.1Hz, 3H), 0.84 (s, 6H)；ES-LCMS m/z 520.1(M+H).
Embodiment 49：1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- alcohol
During 15 minutes, to the 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) at 0 DEG C, stirred in atmosphere - 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridines (1.1g, 2.86mmol) and NaHCO3 H is added dropwise in the solution of (1.679g, 19.99mmol) in acetone (15mL) and water (5.00mL)2O2(0.971g,8.57mmol)。 At 20 DEG C, stirring reaction mixture 12 hours.The NaHSO of saturation is added into the solution3Solution.Organic extract will be merged Salt water washing is used, through MgSO4It is dried, filtered and concentrated.By preparing TLC (PE/EA=1：1,Rf=residue 0.6) is purified, obtain To 5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- alcohol (0.6g, 1.744mmol, yield of light yellow solid 61.1%)：1H NMR(400MHz,CDCl3) δ 7.39-7.37 (m, 2H), 7.30 (d, J=2.4Hz, 1H), 6.87-6.84 (m, 2H), 6.70 (d, J=2.4Hz, 1H), 5.38 (br, 1H), 5.31 (s, 2H), 4.03-4.01 (m, 2H), 3.78 (s, 3H), 1.44 (t, J=7.0Hz, 3H)；ES-LCMS m/z 276.1(M+H).
Step 2：3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4-nitrophenoxy) pyridine
To at 20 DEG C, in N2The fluoro- 4- nitrobenzene (141mg, 0.999mmol) of 1- of lower stirring and 5- ethyoxyls -6- Disposably add in ((4- methoxy-benzyls) epoxide) solution of pyridine -3- alcohol (250mg, 0.908mmol) in MeCN (20mL) Enter Cs2CO3(888mg,2.72mmol).At 80 DEG C, stirring reaction mixture 12 hours.The mixture is filtered, it is dense in a vacuum Contracting filtrate, and pass through silica gel column chromatography (PE/EA=3:1) residue is purified.TLC (PE/EA=3 will be passed through:1,Rf0.5) send out Now all fractions comprising product merge, and concentrate, and obtain 3- ethyoxyls -2- ((4- methoxy-benzyls) oxygen of light yellow solid Base) -5- (4-nitrophenoxy) pyridine (250mg, 0.378mmol, yield 41.7%)：1H NMR(400MHz,CDCl3)δ8.20 (d, J=9.2Hz, 2H), 7.57 (d, J=2.4Hz, 1H), 7.44 (d, J=8.8Hz, 2H), 7.00 (d, J=9.2Hz, 2H), 6.91 (d, J=8.8Hz, 2H), 6.82 (d, J=2.4Hz, 1H), 5.40 (s, 2H), 4.03-4.01 (m, 2H), 3.80 (s, 3H), 1.44 (t, J=7.0Hz, 3H)；ES-LCMS m/z 397.1(M+H).
Step 3：3- (4- isocyanatos -2- (trifluoromethyl) phenoxy group) -3- methy oxetanes
To at 20 DEG C, in N24- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene of lower stirring It is disposable in solution of the amine (100mg, 0.405mmol) in THF (6mL) to add triphosgene (42.0mg, 0.142mmol). At 60 DEG C, the reactant mixture is stirred 2 hours.Step 4：5- (4- amino-benzene oxygens) -3- ethoxy pyridines -2 (1H) -one
At room temperature, 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4-nitrophenoxy) pyridine is stirred The mixture of (250mg, 0.631mmol) and Pd/C (6.71mg, 0.063mmol, 10%) in MeOH (15mL).Use H-(setting：20 DEG C, flow velocity) and it is used as the 10%Pd/C hydrogenations of catalyst.TLC shows that mixture is completed.Filtering should Mixture, and concentrate filtrate in a vacuum, obtain 5- (4- amino-benzene oxygens) -3- ethoxy pyridines -2 (1H) of brown solid - Ketone (100mg, 0.268mmol, yield 42.5%)：1H NMR(400MHz,CDCl3)δ6.80-6.78(m,2H),6.66-6.63 (m, 4H), 3.99-3.97 (m, 2H), 3.56 (br, 2H), 1.48 (t, J=7.0Hz, 3H)；ES-LCMS m/z 247.1(M+ H)。
Step 5：1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To at 40 DEG C, in N2Lower stirring 5- (4- amino-benzene oxygens) -3- ethoxy pyridines -2 (1H) -one (100mg, 0.406mmol), DMAP (2.480mg, 0.020mmol) and Et3N (0.170mL, 1.218mmol) is molten in THF (15mL) In liquid it is disposable add 3- (4- isocyanatos -2- (trifluoromethyl) phenoxy group) -3- methy oxetanes (222mg, 0.812mmol).At 40 DEG C, stirring reaction mixture 1 hour.The solution is concentrated in a vacuum, and by preparing HPLC (MeCN/H2O is used as eluent, alkalescence condition) purifying residue, obtain 1- (the 4- ((5- ethyoxyl -6- oxygen of white-yellowish solid Generation -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (fluoroforms Base) phenyl) urea (126.16mg, 0.234mmol, yield 57.5%)：1H NMR(400MHz,CD3OD) δ 7.75 (d, J= 2.4Hz, 1H), 7.53-7.50 (m, 1H), 7.40-7.36 (m, 2H), 6.96 (dd, J=2.0Hz, 6.8Hz, 2H), 6.83 (d, J =2.4Hz, 1H), 6.74 (d, J=2.8Hz, 1H), 6.61 (d, J=8.8Hz, 1H), 4.89-4.83 (m, 2H), 4.63 (d, J =7.2Hz, 2H), 4.00-3.97 (m, 2H), 1.71 (s, 3H), 1.42 (t, J=7.0Hz, 3H)；ES-LCMS m/z 520.1 (M+H)。
Embodiment 50：1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) - 3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea hydrochloride
Step 1：The bromo- 5- ethoxy pyridines of 3-
At room temperature, K is added into mixture of the 5- bromopyridine -3- alcohol (45g, 259mmol) in DMF (400mL)2CO3 (71.5g, 517mmol) and EtI (48.4g, 310mmol).At 70 DEG C, the mixture is stirred 12 hours.LCMS and TLC (PE/ EA=5:1, Rf 0.4) display reaction is completed.The mixture is filtered, filtrate is concentrated in a vacuum, and residue is purified by post, Obtain the bromo- 5- ethoxy pyridines of 3- (30g, 135mmol, yield 52.2%)：1H NMR(400MHz,CD3OD) δ 8.18 (d, J= 2.8Hz, 2H), 7.59 (d, J=2.4Hz, 1H), 4.11 (d, J=7.2Hz, 2H), 1.40 (t, J=7.2Hz, 3H)；ES-LCMS m/z 204(M+2H)。
Step 2：The bromo- 5- ethoxy pyridines 1- oxides of 3-
M-CPBA is added into mixture of the bromo- 5- ethoxy pyridines (28g, 139mmol) of 3- in DCM (500mL) (28.7g,166mmol).At 20 DEG C, the mixture is stirred 10 hours.LCMS and TLC (DCM/MeOH=40:1,Rf 0.4) Display reaction is completed.Use NaSO3With the NaHCO of saturation3Solution washs the mixture.The organic extract of merging is washed with salt Wash, through MgSO4It is dried, filtered and concentrated, obtains 3- bromo- 5- ethoxy pyridines 1- oxides (30g, 128mmol, yield 92%)：1H NMR(400MHz,CD3OD) δ 8.16 (d, J=3.2Hz, 1H), 8.05 (d, J=3.6Hz, 1H), 7.47 (d, J= 3.2Hz, 1H), 4.12 (d, J=7.2Hz, 2H), 1.38 (t, J=7.2Hz, 3H)；ES-LCMS m/z 220(M+2H).
Step 3：The bromo- 2- chloro-3-ethoxies pyridines of 5-
Added into mixture of the bromo- 5- methoxypyridines 1- oxides (28g, 128mmol) of 3- in DCM (300mL) POCl3(168mL,1798mmol).At 40 DEG C, the mixture is stirred 12 hours.LCMS and TLC (PE/EA=5:1,Rf 0.6) display reaction is completed.The mixture is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution.By organic extraction of merging Thing salt water washing is taken, through MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10:1) purify, obtain 5- Bromo- 2- chloro-3-ethoxies pyridine (26g, 106mmol, yield 82%)：1H NMR(400MHz,CD3OD) δ 8.00 (d, J= 2.0Hz, 1H), 7.65 (d, J=2.0Hz, 1H), 4.16 (d, J=7.2Hz, 2H), 1.43 (t, J=7.2Hz, 3H)；ES-LCMS m/z 238(M+2H)。
Step 4：The bromo- 3- ethoxy pyridines of 2- (benzyloxy) -5-
Into mixture of the bromo- 2- chloro-3-ethoxies pyridines (700mg, 2.96mmol) of 5- in phenyl methanol (10mL) Add sodium (340mg, 14.80mmol).At 100 DEG C, the mixture is stirred 3 hours.LCMS display reactions are completed.It is diluted with water The mixture, and the mixture is extracted with EA, concentrate in a vacuum, and pass through silica gel column chromatography (PE/EA=5:1) purify remaining Thing, obtains the bromo- 3- ethoxy pyridines of 2- (benzyloxy) -5- (751mg, 2.193mmol, yield 74.1%)：1H NMR (400MHz,CDCl3) δ 7.74 (d, J=6.8Hz, 1H), 7.46 (d, J=2.0Hz, 2H), 7.36-7.24 (m, 3H), 7.13 (d, J=2.4Hz, 1H), 5.43 (s, 2H), 4.07 (d, J=6.8Hz, 2H), 1.44 (t, J=6.8Hz, 3H)；ES-LCMS m/ z 309(M+2H)。
Step 5：2- (benzyloxy) -3- ethyoxyls -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- Base) pyridine
To at 20 DEG C, in N2The bromo- 3- ethoxy pyridines (1.5g, 4.87mmol) of 2- (benzyloxy) -5- of lower stirring, 4, 4,4', 4', 5,5,5', 5'- prestox -2,2'- double (1,3,2- dioxaborolans alkane) (1.483g, 5.84mmol) and It is disposable in solution of the KOAc (0.955g, 9.73mmol) in 1,4- dioxanes (15mL) to add PdCl2(dppf) (0.178g,0.243mmol).At 100 DEG C, the reactant mixture is stirred 3 hours.The solution is concentrated in a vacuum, and is passed through Silica gel column chromatography (PE/EA=5:1) residue is purified.TLC (PE/EA=5 will be passed through:1,Rf=0.6) find comprising product All fractions merge, and concentrate, obtain light yellow oil 2- (benzyloxy) -3- ethyoxyls -5- (4,4,5,5- tetramethyls - 1,3,2- dioxaborolan alkane -2- bases) pyridine (1.2g, 1.858mmol, yield 38.2%)：1H NMR(400MHz, CDCl3) δ 8.10 (s, 1H), 7.48 (d, J=7.6Hz, 2H), 7.35-7.26 (m, 4H), 5.50 (s, 2H), 4.13-4.08 (m, 2H), 1.48 (t, J=7.0Hz, 3H), 1.32 (s, 12H)；ES-LCMS m/z 356.2(M+H).
Step 6：The pyridines of 6'- (benzyloxy) -5'- ethyoxyl -6- methyl-5-nitros -2,3'- two
To at 20 DEG C, in N22- (the benzyloxy) -3- ethyoxyls -5- (4,4,5,5- tetramethyls -1,3,2- two of lower stirring Oxa- boron heterocycle pentane -2- bases) pyridine (491mg, 1.382mmol), the bromo- 2- Methyl-3-nitropyridines of 6- (250mg, 1.152mmol) and Cs2CO3In the solution of (938mg, 2.88mmol) in 1,4- dioxanes (6ml) and water (2.000ml) once Property add PdCl2(dppf)(42.1mg,0.058mmol).Reaction vessel is sealed, and using initial in CEM discover 100W is heated to 110 DEG C 15 minutes.After cooling, reactant is concentrated in a vacuum, and passes through TLC (DCM:MeOH=10:1, Rf=residue 0.5) is purified, obtain desired product 6'- (benzyloxy) -5'- ethyoxyl -6- methyl-5-nitros -2,3'- bis- Pyridine (250mg, 0.643mmol, yield 55.8%)：1H NMR(400MHz,CDCl3)δ8.36-8.34(m,2H),7.87(d,J =2.0Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.50-7.48 (m, 2H), 7.38-7.29 (m, 3H), 5.55 (s, 2H), 4.24-4.19 (m, 2H), 2.93 (s, 3H), 1.50 (t, J=7.0Hz, 3H)；ES-LCMS m/z 366.1(M+H).
Step 7：5- amino -5'- ethyoxyl -6- methyl-[2,3'- bipyridyls] -6'(1'H) -one
At room temperature, the pyridine of stirring 6'- (benzyloxy) -5'- ethyoxyl -6- methyl-5-nitros -2,3'- bis- (250mg, 0.684mmol) with mixtures of the 10%Pd/C (7.28mg, 0.068mmol) in MeOH (15mL).Use H-cube (settings： 20 DEG C, flow velocity) and it is used as the 10%Pd/C hydrogenations of catalyst.TLC shows that mixture is completed.Filter the mixture, and Filtrate is concentrated in vacuum, 5- amino -5'- ethyoxyl -6- methyl-[2,3'- bipyridyl] -6'(1'H of yellow oil is obtained) - Ketone (150mg, 0.605mmol, yield 88%)：1H NMR(400MHz,CDCl3) δ 7.27 (d, J=2.8Hz, 2H), 7.10 (d, J =8.0Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 4.04-3.99 (m, 2H), 3.86 (br, 2H), 2.32 (s, 3H), 1.38 (t, J=7.0Hz, 3H)；ES-LCMS m/z 246.1(M+H).
Step 8：3- (4- isocyanatos -2- (trifluoromethyl) phenoxy group) -3- methy oxetanes
To at 20 DEG C, in N24- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene of lower stirring It is disposable in solution of the amine (50mg, 0.202mmol) in THF (6mL) to add triphosgene (21.01mg, 0.071mmol). At 60 DEG C, the reactant mixture is stirred 2 hours.
Step 9：1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea hydrochloride
To at 40 DEG C, in N25- amino -5'- ethyoxyl -6- methyl-[2,3'- bipyridyls] -6'(1'H of lower stirring) - Ketone (40mg, 0.163mmol), DMAP (0.996mg, 8.15 μm of ol) and Et3N (0.068mL, 0.489mmol) is at THF (10mL) In solution in disposable add 3- (4- isocyanatos -2- (trifluoromethyl) phenoxy group) -3- methy oxetanes (66.8mg,0.245mmol).At 40 DEG C, stirring reaction mixture 1 hour.Concentrate solution, and by preparing in a vacuum HPLC(MeCN/H2O is used as eluent, acid condition) purifying residue, obtain the 1- (5'- ethyoxyl -6- first of yellow solid Base -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) - 3- (trifluoromethyl) phenyl) urea hydrochloride (41.7mg, 0.074mmol, yield 45.2%)：1H NMR(400MHz,CD3OD)δ 8.97 (d, J=8.8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 7.85 (d, J=2.8Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 7., 58 (dd, J=2.4Hz, 8.8Hz, 1H), 7.37 (d, J=2.0Hz, 1H), 6.65 (d, J=9.2Hz, 1H), 4.89- 4.88 (m, 2H), 4.64 (d, J=7.6Hz, 2H), 4.18-4.12 (m, 2H), 2.77 (s, 3H), 1.72 (s, 3H), 1.50 (t, J =7.0Hz, 3H)；ES-LCMS m/z 519.2(M+H).
Embodiment 51：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea
Step 1：4- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxas Boron heterocycle pentane -2- bases) pyridine
During 1 minute, at -70 DEG C, in N2The bromo- 4- ethyoxyls -2- of 5- ((4- methoxy-benzyls) oxygen of lower stirring Base) n-BuLi (7.81mL, 19.52mmol) is added portionwise in solution of the pyridine (5.5g, 16.26mmol) in THF (40mL). At -70 DEG C, stirring reaction mixture 1 hour.Then, at -70 DEG C, the 4- second added into the solution in THF (1mL) Epoxide -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyrrole Pyridine (1.7g, 4.41mmol, yield 27.1%) is stirred simultaneously.At -70 DEG C, the solution is stirred 1 hour.Added into the solution The NH of saturation4Cl solution.Then, the solution is concentrated, and is distributed between EA and water.The organic extract of merging is washed with salt Wash, through Na2SO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=5:1) residue is purified.TLC (PE/ will be passed through EA=5:1,Rf=0.4) find that all fractions comprising product merge, and concentrate, obtain the 4- ethyoxyls of light yellow oil- 2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (1.7g, 4.41mmol, yield 27.1%)：1H NMR(400MHz,CDCl3) δ 8.28 (s, 1H), 7.37 (d, J=8.4Hz, 2H), 6.88 (d, J=8.6Hz, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 4.00 (q, J=6.8Hz, 2H), 3.80 (s, 3H), 1.40 (t, J=6.9Hz, 3H), 1.32 (s, 12H)；ES-LCMS m/z 386.2(M+H).
Step 2：The chloro- 4- methylpyrimidines -5- amine of 2-
To at 20 DEG C, in N2The chloro- 6- methyl-5-nitros pyrimidines (20g, 96mmol) of 2,4- bis- of lower stirring and NH4Cl It is disposable in the solution of (51.4g, 962mmol) in MeOH (600mL) to add zinc (62.9g, 962mmol).At 70 DEG C, stir Mix the reactant mixture 50 hours.The mixture is filtered, and concentrates filtrate in a vacuum, and passes through silica gel column chromatography (DCM/ MeOH=30:1) residue is purified.TLC (EA/EA=1=1 will be passed through：1, Rf 0.6) all grades of divisions for including product are found And, and concentrate, obtain the chloro- 4- methylpyrimidines -5- amine of 2- (1.8g, 12.54mmol, yield 13.04%) of light yellow solid：1H NMR(400MHz,CD3OD-d4)δ7.92(s,1H),2.33(s,3H)；ES-LCMS m/z 144.1(M+1).
Step 3：The chloro- 5- isocyanatos -4- methylpyrimidines of 2-
To at 20 DEG C, in N2The chloro- 4- methylpyrimidines -5- amine (250mg, 1.741mmol) of 2- of lower stirring are in THF It is disposable in solution in (8mL) to add triphosgene (181mg, 0.609mmol).At 60 DEG C, the reactant mixture 30 is stirred Minute.ES-LCMS m/z 202.1(M+32).
Step 4：1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea
To at 40 DEG C, in N2Lower stirring 1- (4- amino -2- (trifluoromethyl) phenyl) ethyl ketone dihydrochloride (300mg, 1.087mmol), DMAP (398mg, 3.26mmol) and Et3One in solution of the N (7.57 μ L, 0.054mmol) in THF (6mL) Secondary property adds the chloro- 5- isocyanatos -4- methylpyrimidines (240mg, 1.413mmol) of 2-.At 40 DEG C, stirring reaction mixture 1 Hour.Then, the solution is concentrated, and by preparing TLC (PE/EA=1：1,Rf0.2) residue is purified, obtains light yellow solid Body 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea (30mg, 0.080mmol, Yield 7.41%)：1H NMR(400MHz,CD3OD-d4)δ9.05(s,1H),7.97(s,1H),7.79-7.69(m,2H),2.56 (s,3H),2.51(s,3H)；ES-LCMS m/z 373.1(M+H).
Step 5：1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) Epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N2(4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) boric acid of lower stirring (73.2mg, 0.241mmol), 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea (90mg, 0.241mmol) and Cs2CO3(197mg, 0.604mmol) is molten in 1,4- dioxanes (3mL) and water (1.000mL) It is disposable in liquid to add PdCl2(PPh3)2(8.47mg,0.012mmol).Reaction vessel is sealed, and in CEM Discover 110 DEG C are heated to using initial pattern 20 minutes.After cooling, concentrated reaction solution, and distribute between EA and water.It will close And organic extract salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing TLC (DCM/MeOH=10:1,Rf =0.6) purify residue, obtain brown solid 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls - 6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (30mg, 0.050mmol, yield 20.86%)：1H NMR(400MHz,CDCl3) δ 9.12 (s, 1H), 8.45 (s, 1H), 8.21 (br.s., 1H), 7.77 (d, J= 8.5Hz, 1H), 7.66 (s, 1H), 7.50 (d, J=8.5Hz, 1H), 7.38 (d, J=8.5Hz, 2H), 7.30 (br.s., 1H), 6.89 (d, J=8.5Hz, 2H), 6.32 (s, 1H), 5.33 (s, 2H), 4.10 (q, J=6.9Hz, 2H), 3.81 (s, 3H), 2.59 (s, 3H), 2.50 (s, 3H), 1.37 (t, J=7.0Hz, 3H)；ES-LCMS m/z 596.1(M+H).
Step 6:1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N2Lower stirring 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls - 6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (50mg, 0.084mmol) is in DCM It is disposable in solution in (10mL) to add MeMgBr (0.168mL, 0.504mmol).At 20 DEG C, stirring reaction mixture 1 Hour.The NH of saturation is added into the solution4Cl solution.Concentrate the mixture.By preparing TLC (DCM/MeOH=10:1,Rf =residue 0.4) is purified, obtain the impure product of light yellow solid.By it by preparing HPLC (MeCN/H2O is used as elution Liquid, acid condition) purifying, obtain 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- first of white solid Yl pyrimidines -5- bases) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea (4.18mg, 8.28 μm of ol, yield 9.87%).TLC (DCM/MeOH=10:1,Rf=0.4):1H NMR(400MHz,CD3OD-d4)δ9.16(s,1H),7.88(s, 1H), 7.77 (s, 1H), 7.66 (s, 2H), 5.99 (s, 1H), 4.11 (q, J=7.0Hz, 2H), 2.55 (s, 3H), 1.61 (s, 6H), 1.36 (t, J=6.9Hz, 3H)；ES-LCMS m/z492.(M+1).
Embodiment 52：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
Step1：1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N2The 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - It is disposable in solution of the 4- methylpyrimidine -5- carboxylic acids (0.2g, 0.506mmol) in 1,4- dioxanes (3mL) to add Et3N (0.106mL, 0.759mmol) and DPPA (0.167g, 0.607mmol).At room temperature, the reactant mixture is stirred 30 minutes. Into the mixture, add 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline (0.122g, 0.506mmol) and exist Solution in 1mL 1,4- dioxanes.The reaction solution is heated to 100 DEG C, while stirring 3 hours.Concentration should in a vacuum Solution, and by preparing TLC (DCM/MeOH=10:1,Rf=residue 0.5) is purified, obtain the 1- (2- (4- of white-yellowish solid Ethyoxyl -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl isophthalic acid H- miaows Azoles -1- bases) -5- (trifluoromethyl) phenyl) urea (60mg, 0.095mmol, yield 18.7%)：1H NMR(400MHz,CD3OD)δ 9.18(s,1H),9.15(s,1H),8.39(s,1H),8.25(s,1H),8.04(s,1H),7.81(s,1H),7.54(s,1H), 7.25-7.23(m,2H),6.87-6.85(m,2H),6.48(s,1H),5.31(s,2H),4.13-4.10(m,2H),3.79(s, 3H),2.82(s,3H),2.59(s,3H),1.40-1.36(m,3H)；ES-LCMS m/z 634.2(M+H).
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N21- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- of lower stirring Base) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea (70mg, The HCl (0.5mL, 2.000mmol) in MeOH 0.110mmol) is disposably added in the solution in DCM (5mL).At 20 DEG C Under, stir the reactant mixture 1 hour.Then, concentrate solution.By preparing HPLC (instruments: DC/ posts: ASB C18 150* 25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：32-62 (B%)) Residue is purified, obtaining the 1- of white-yellowish solid, (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl is phonetic Pyridine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea dihydrochloride (17.58mg, 0.030mmol, yield 27.0%).TLC (DCM/MeOH=5:1,Rf=0.4):1HNMR(400MHz,CD3OD)δ9.49(s, 1H),9.47-9.44(m,1H),8.41(s,1H),8.18(s,1H),8.06(s,1H),7.88(s,1H),7.75(s,1H), 6.18 (s, 1H), 4.35 (d, J=7.2Hz, 2H), 2.79 (s, 3H), 2.45 (s, 3H), 1.48 (t, J=6.9Hz, 3H)；ES- LCMS m/z 514.2(M+H)。
Embodiment 53：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidines -5- Base) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
Step 1：4,6- dimethyl -2- oxo -1,2,5,6- tetrahydropyrimidine -5- carboxylic acid, ethyl esters
In 350mL pressure flasks, by ethyl 3-oxobutanoate (16.27g, 125mmol), acetaldehyde (5.51g, 125mmol), the mixture of urea (7.51g, 125mmol) and ice AcOH (1mL, 17.47mmol) in EtOH (35mL) is heated to 90 DEG C overnight.The mixture is diluted with water.Precipitation is collected by filtration, is washed with water and air-dries, the 4,6- of white solid are obtained Dimethyl -2- oxo -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid, ethyl esters (12g, 60.5mmol, yield 48.4%)：1H NMR (400MHz,DMSO-d6)δ8.95(br.s.,1H),7.18(br.s.,1H),4.13-3.95(m,3H),2.12(s,3H), 1.16 (t, J=7.0Hz, 3H), 1.06 (d, J=6.4Hz, 3H)；LCMS m/z 199.0(M+H).
Step 2：4,6- dimethyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters
To at 0 DEG C, in N24,6- dimethyl -2- oxygen is added portionwise in the nitric acid (12mL, 17.66mmol) of lower stirring Generation -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid, ethyl esters (3.5g, 17.66mmol).At 0 DEG C, 10 points of the reactant mixture is stirred Clock.In the frozen water that the reaction solution is poured into 60g, then extracted with EA.By the organic extract of merging salt water washing, warp Na2SO4It is dried, filtered and concentrated.Obtain 4,6- dimethyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (2.6g, 13.25mmol, yield 75%).TLC (PE/EA=5:1,Rf=0.6):1H NMR(400MHz,CDCl3)δ13.71-13.48 (m, 1H), 4.36 (q, J=7.1Hz, 2H), 2.56 (s, 6H), 1.38 (t, J=7.1Hz, 3H)；ES-LCMS m/z 197.1(M +H)。
Step 3：The chloro- 4,6- dimethyl pyrimidines -5- carboxylic acid, ethyl esters of 2-
To at 20 DEG C, in N2The POCl of lower stirring3(10.42mL, 122mmol) and DIEA's (33mL, 189mmol) is molten 4,6- dimethyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (2.4g, 12.23mmol) are slowly added in liquid.80 At DEG C, the reactant mixture is stirred 2 hours.Then, the solution is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution. By the organic extract of merging salt water washing, through Na2SO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10: 1) residue is purified.TLC (PE/EA=10 will be passed through:1,Rf=0.7) find that all fractions comprising product merge, and concentrate, Obtain the chloro- 4,6- dimethyl pyrimidines -5- carboxylic acid, ethyl esters of 2- (1.6g, 7.45mmol, yield 60.9%) of yellow oil：1H NMR(400MHz,CDCl3) δ 4.43 (q, J=6.8Hz, 2H), 2.54 (s, 6H), 1.40 (t, J=7.1Hz, 3H)；ES-LCMS m/z 215.1(M+H)。
Step 4：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4,6- dimethyl pyrimidines -5- Carboxylic acid, ethyl ester
To at 20 DEG C, in N23- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- of lower stirring Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (2.51g, 6.52mmol), the chloro- 4,6- dimethyl pyrimidines -5- of 2- Carboxylic acid, ethyl ester (1.4g, 6.52mmol) and Cs2CO3(4.25g, 13.04mmol) is in 1,4- dioxanes (15mL) and water (5.00mL) In solution in disposable add PdCl2(dppf)(0.477g,0.652mmol).At 110 DEG C, the reaction vessel 2 is heated small When.Then, solution is concentrated, and distributed between EA and water.By the organic extract of merging salt water washing, through MgSO4It is dry It is dry, filter and concentrate.Pass through silica gel column chromatography TLC (PE/EA=10:1,5:1) residue is purified.TLC (PE/EA=will be passed through 2：1, Rf0.5) find that all fractions comprising product merge, and concentrate, obtain the 2- (5- ethyoxyls -6- of light yellow solid ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4,6- dimethyl pyrimidine -5- carboxylic acid, ethyl esters (1.7g, 3.89mmol, yield 59.6%)：1H NMR(400MHz,CDCl3)δ8.86-8.82(m,1H),8.08-8.04(m,1H),7.48-7.42(m,2H), 6.87 (d, J=8.6Hz, 2H), 5.49 (s, 2H), 4.43 (s, 2H), 4.23-4.15 (m, 2H), 3.79 (s, 3H), 2.58 (s, 6H), 1.52-1.45 (m, 3H), 1.41 (t, J=7.1Hz, 3H)；LCMS m/z 438.2(M+H).
Step 5：2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- carboxylic acids
To at 20 DEG C, in N2The 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - It is disposable in solution of the 4,6- dimethyl pyrimidine -5- carboxylic acid, ethyl esters (500mg, 1.143mmol) in THF (5mL) to add NaOH (2.5mL,6.25mmol).At 100 DEG C, the reactant mixture is stirred 12 hours.Then, concentrate solution, and neutralized with dense HCl To pH=7.0, stir simultaneously.Then filter, and filter cake is washed with water (10mL).Filter cake is dried in a vacuum, yellow-white is obtained Solid 2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- carboxylic acids (300mg, 1.037mmol, yield 91%).TLC (DCM/MeOH=10:1,Rf 0.4):1HNMR(400MHz,CD3OD) δ 8.16 (d, J= 2.0Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 4.18-4.12 (m, 2H), 2.59-2.56 (m, 6H), 1.47 (t, J= 6.9Hz,3H)；LCMS m/z 290.2(M+H).
Step 6：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) - 3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N22- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- diformazans of lower stirring Yl pyrimidines -5- carboxylic acids (150mg, 0.519mmol), 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline (125mg, 0.519mmol) and Et3N (79mg, 0.778mmol) is disposably added in the solution in 1,4- dioxanes (5mL) DPPA (171mg, 0.622mmol).The reactant mixture is heated to 80 DEG C 1 hour.Then, concentrate solution.By preparing HPLC (instruments: DC/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/ The distribution description of min/ gradients：15-55 (B%)) purifying residue, obtain white-yellowish solid 1- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (fluoroforms Base) phenyl) urea dihydrochloride (11.53mg, 3.67%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz, CD3OD)δ9.44-9.40(m,1H),8.27-8.23(m,1H),8.20(s,1H),7.92(s,2H),7.84(s,1H),7.69 (s, 1H), 4.17 (d, J=6.8Hz, 2H), 2.57 (s, 6H), 2.44 (s, 3H), 1.48 (t, J=6.9Hz, 3H)；ES-LCMS m/z 528.2(M+H)。
Embodiment 54：1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step1：1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
At 20 DEG C, in N2Under, to 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl It is disposable in solution of the pyrimidine -5-carboxylic acid (200mg, 0.506mmol) in 1,4- dioxanes (5mL) to add Et3N (0.106mL, 0.759mmol) and DPPA (167mg, 0.607mmol).At room temperature, the reactant mixture is stirred 30 minutes.To In the solution, solution of 4- chloro- 3- (trifluoromethyl) aniline (79mg, 0.405mmol) in the 1mL dioxane of Isosorbide-5-Nitrae-is added. The reaction solution is heated to 100 DEG C 3 hours, stirred simultaneously.The solution is concentrated in a vacuum, and by preparing TLC (DCM/ MeOH=20:1,Rf=residue 0.5) is purified, obtain 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- of white-yellowish solid (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (25mg, 0.043mmol, Yield 8.41%)：1H NMR(400MHz,CD3OD)δ9.18(s,1H),8.27(s,1H),8.00(s,1H),7.92(br.s., 1H),7.85(s,1H),7.39-7.26(m,2H),6.92-6.90(m,2H),6.48(s,1H),5.30(s,2H),4.17- 4.15(m,2H),3.79(s,3H),2.58(s,3H),1.42-1.39(m,3H)；ES-LCMS m/z 588.1(M+H).
Step 2：1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N21- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- of lower stirring ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (25mg, 0.043mmol) is in DCM (2mL) Solution in disposably add the HCl (0.5mL, 2.000mmol) in MeOH.At 20 DEG C, stirring reaction mixture 1 is small When.Then, concentrate solution.By preparing HPLC (instruments: DC/ posts: ASB C18 150*25mm/ mobile phase As: water+0.1% HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：33-63 (B%)) purifying residue, obtain yellow-white 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- first of solid Yl pyrimidines -5- bases) urea hydrochloride (6.15mg, 0.012mmol, yield 28.5%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz,CD3OD) δ 9.50 (s, 1H), 8.39 (s, 1H), 8.07 (d, J=2.2Hz, 1H), 7.68-7.62 (m, 1H), 7.55 (d, J=8.6Hz, 1H), 6.15 (s, 1H), 4.34 (q, J=6.8Hz, 2H), 2.75 (s, 3H), 1.47 (t, J= 6.9Hz,3H)；ES-LCMS m/z 468(M+H).
Embodiment 55：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：(6- (benzyloxy) -4- ethoxy pyridine -3- bases) boric acid
During 1 minute, at -70 DEG C, in N22- (the benzyloxy) -4- ethyoxyl -5- iodine pyridines stirred under atmosphere N-BuLi (0.619mL, 1.549mmol) is added portionwise in the solution of (500mg, 1.408mmol) in THF (12mL).- 70 At DEG C, stirring reaction mixture 1 hour.Then, at -70 DEG C, the 2- in THF (1mL) is slowly added into the solution Isopropoxy -4,4,5,5- tetramethyls -1,3,2- dioxaborolans alkane (288mg, 1.549mmol) is stirred simultaneously.- At 70 DEG C, the solution is stirred 1 hour.The NH of saturation is added into the mixture4Cl solution.Then, the solution is concentrated, and is distributed Between EA and water.By the organic extract of merging salt water washing, through Na2SO4It is dried, filtered and concentrated.Obtain (6- (benzyloxies Base) -4- ethoxy pyridine -3- bases) boric acid (300mg, 1.099mmol, yield 78%).TLC (PE/EA=2：1,Rf=0.4):1H NMR(400MHz,CDCl3)δ8.21(br.s.,1H),7.46-7.22(m,5H),6.15(br.s.,1H),5.26(br.s., 2H), 4.02 (d, J=6.8Hz, 2H), 1.41 (t, J=6.7Hz, 3H)；ES-LCMS m/z274.1(M+1).
Step 2：The chloro- 4- methylpyrimidines -5- amine of 2-
To at 20 DEG C, in N2The chloro- 6- methyl-5-nitros pyrimidines (20g, 96mmol) of 2,4- bis- stirred under atmosphere and 20 It is disposable in the solution of (51.4g, 962mmol) in MeOH (600mL) to add zinc (62.9g, 962mmol).At 70 DEG C, stir Mix reactant mixture 50 hours.The mixture is filtered, filtrate is concentrated in a vacuum, and pass through silica gel column chromatography (DCM/MeOH= 30:1) residue is purified.TLC (PE/EA=1=1 will be passed through：1, Rf=0.6) find that all fractions comprising product merge, and Concentration, obtains the chloro- 4- methylpyrimidines -5- amine of 2- (1.8g, 12.54mmol, yield 13.04%) of light yellow solid：1H NMR (400MHz,CD3OD)δ7.92(s,1H),2.33(s,3H)；ES-LCMS m/z144.1(M+H).
Step 3：The chloro- 5- isocyanatos -4- methylpyrimidines of 2-
To at 20 DEG C, in N2The chloro- 4- methylpyrimidines -5- amine (250mg, 1.741mmol) of 2- stirred under atmosphere are in THF It is disposable in solution in (8mL) to add triphosgene (181mg, 0.609mmol).At 60 DEG C, the reactant mixture 30 is stirred Minute.ES-LCMS m/z 202.1(M+32).
Step 4：1- (the chloro- 4- methylpyrimidines -5- bases of 2-) -3- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) benzene Base) urea
To at 40 DEG C, in N24- ((dimethylamino) methyl) -3- (trifluoromethyl) the aniline disalt stirred under atmosphere Hydrochlorate (200mg, 0.687mmol), DMAP (252mg, 2.061mmol) and Et3N (4.79 μ L, 0.034mmol) is at THF (6mL) In solution in disposable add the chloro- 5- isocyanatos -4- methylpyrimidines (175mg, 1.030mmol) of 2-.At 40 DEG C, stirring Reactant mixture 1 hour.Then, the solution is concentrated, and by preparing TLC (PE/EA=1：1,Rf0.2) residue is purified, is obtained To 1- (the chloro- 4- methylpyrimidines -5- bases of 2-) -3- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) benzene of light yellow solid Base) urea (210mg, 0.542mmol, yield 79%)：1H NMR(400MHz,CD3OD)δ9.05(s,1H),8.08(s,1H), 7.83-7.78 (m, 1H), 7.71 (d, J=8.4Hz, 1H), 4.31 (br.s., 2H), 2.83-2.77 (m, 6H), 2.53 (s, 3H)；ES-LCMS m/z 388.1(M+H).
Step 5：1- (2- (6- (benzyloxy) -4- ethoxy pyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((two Methylamino) methyl) -3- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N2Stirred under atmosphere (6- (benzyloxy) -4- ethoxy pyridine -3- bases) boric acid (127mg, 0.464mmol), 1- (the chloro- 4- methylpyrimidines -5- bases of 2-) -3- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) Urea (150mg, 0.387mmol) and Cs2CO3(315mg, 0.967mmol) is in 1,4- dioxanes (9mL) and water (3.00mL) It is disposable in solution to add PdCl2(PPh3)2(13.58mg,0.019mmol).Reaction vessel is sealed, and in CEM In Discover 110 DEG C are heated to using initial pattern 20 minutes.After cooling, solution is concentrated, and distributed in EA and water Between.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography TLC (PE/EA=1：1) residue is purified.TLC (PE/EA=1 will be passed through：1, Rf=0.3) find to include all grades of divisions of product And, and concentrate, obtain the 1- (2- (6- (benzyloxy) -4- ethoxy pyridine -3- bases) -4- methylpyrimidine -5- bases) of brown solid - 3- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) urea (30mg, 0.052mmol, yield 13.36%)：1H NMR(400MHz,CDCl3)δ10.11(br.s.,1H),9.31(s,1H),8.62(br.s.,1H),8.45(s,1H),8.15 (d, J=8.4Hz, 1H), 7.46 (d, J=7.5Hz, 2H), 7.41-7.34 (m, 2H), 7.32 (d, J=7.3Hz, 1H), 6.33 (s, 1H), 5.41 (s, 2H), 4.30 (s, 2H), 4.09 (q, J=7.1Hz, 2H), 2.81 (s, 6H), 2.72 (s, 3H), 1.37 (t, J=6.9Hz, 3H)；ES-LCMS m/z 581.0(M+H).
Step 6：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N21- (2- (6- (benzyloxy) -4- ethoxy pyridine -3- bases) -4- methyl stirred under atmosphere Pyrimidine -5- bases) -3- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) urea (30mg, 0.052mmol) is in MeOH In solution in (10mL) it is disposable add Pd/C (3mg, in water 10%).At 20 DEG C, stirring reaction mixture 12 hours. The mixture is filtered, filtrate is concentrated in a vacuum, and by preparing (MeCN/H2O is used as eluent, acid condition) purifying remnants Thing, obtain light yellow solid 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride (10.86mg, 0.019mmol, yield 36.5%).TLC (DCM/MeOH=10:1,Rf 0.3):1H NMR(400MHz,CD3OD)δ9.49(s,1H),8.38(s,1H), 8.17 (d, J=2.0Hz, 1H), 7.88-7.84 (m, 1H), 7.73 (d, J=8.4Hz, 1H), 6.16 (s, 1H), 4.47 (s, 2H), 4.34 (q, J=6.9Hz, 2H), 2.93 (s, 6H), 2.76 (s, 3H), 1.47 (t, J=7.1Hz, 3H)；ES-LCMS m/ z491.1(M+H)。
Embodiment 56：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- ethyl-pyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
Step 1：6- ethyl-2-oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters
Urea (7.5g, 125mmol), 3- oxopentanoic acid methyl esters (19.80g, 137mmol) are stirred in acton Solution in (20.36g, 137mmol) 28 hours, while at 80 DEG C, in N2EtOH is distilled out under atmosphere.Then, this is mixed Compound is cooled to 20 DEG C, and adds EtOH (50mL), the NaOEt added into above-mentioned mixing in EtOH (50mL) (12.75g, 187mmol), and at 80 DEG C stir the mixture 2 hours, the mixture be cooled to 20 DEG C, be subsequently added into water (100mL), AcOH (10mL) is added at 20-30 DEG C, the mixture is then filtered, solid is washed with water (150mL), dries, obtains 6- second Base -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (12g, 61.2mmol, yield 49.0%).1H NMR(400MHz, DMSO-d6) δ 8.67 (s, 1H), 4.20 (q, J=7.1Hz, 2H), 2.87 (q, J=7.3Hz, 2H), 1.25 (t, J=7.1Hz, 3H), 1.12 (t, J=7.5Hz, 3H)；LCMSm/z 197.0(M+H).
Step 2：The chloro- 4- ethyl-pyrimidines -5- carboxylic acid, ethyl esters of 2-
At room temperature, 4- ethyl-2-oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (2.4g, 12.23mmol) are dissolved in POCl3In (28.1g, 183mmol).The reactant mixture is heated to 80 DEG C 2 hours.The solution is concentrated in a vacuum, and is led to Cross silica gel column chromatography (PE/EA=10:1) residue is purified.TLC (PE/EA=10 will be passed through:1,Rf=0.6) find comprising production All fractions of thing merge, and concentrate, obtain light yellow oil the chloro- 4- ethyl-pyrimidines -5- carboxylic acid, ethyl esters of 2- (0.7g, 3.26mmol, yield 26.7%)：1H NMR(400MHz,CDCl3)δ8.98(s,1H),4.48-4.38(m,2H),3.19-3.13 (m,2H),1.42-1.38(m,3H),1.32-1.28(m,3H)。
Step 3：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- ethyl-pyrimidine -5- carboxylic acids Ethyl ester
To at 20 DEG C, in N23- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- of lower stirring Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (0.897g, 2.329mmol), the chloro- 4- ethyl-pyrimidines -5- carboxylics of 2- Acetoacetic ester (0.5g, 2.329mmol) and Cs2CO3(1.518g, 4.66mmol) is in 1,4- dioxanes (9mL) and water (3.00mL) Solution in disposable add PdCl2(dppf)(0.170g,0.233mmol).At 110 DEG C, heating response container 2 hours. Then, solution is concentrated, and distributed between EA and water.By the organic extract of merging salt water washing, through MgSO4Dry, Filter and concentrate.Pass through silica gel column chromatography (PE/EA=10:1,5:1) residue is purified.TLC (PE/EA=2 will be passed through：1, Rf 0.5) find that all fractions comprising product merge, and concentrate, obtain 2- (5- ethyoxyls -6- ((the 4- methoxies of light yellow solid Base benzyl) epoxide) pyridin-3-yl) -4- ethyl-pyrimidine -5- carboxylic acid, ethyl esters (0.7g, 1.600mmol, yield 68.7%)：1H NMR(400MHz,CDCl3) δ 9.12 (s, 1H), 8.92 (s, 1H), 8.11 (s, 1H), 7.45 (d, J=8.1Hz, 2H), 6.88 (d, J=8.1Hz, 3H), 5.50 (s, 2H), 4.40 (d, J=7.1Hz, 2H), 4.20 (d, J=7.1Hz, 2H), 3.79 (s, 3H), 3.20-3.18 (m, 2H), 1.48 (t, J=6.8Hz, 3H), 1.41 (t, J=7.1Hz, 3H), 1.36 (t, J=7.5Hz, 3H)；LCMS m/z 438.2(M+H).
Step 4：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- ethyl-pyrimidine -5- carboxylic acids
To at 20 DEG C, in N2The 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - In solution of the 4- ethyl-pyrimidine -5- carboxylic acid, ethyl esters (0.7g, 1.600mmol) in MeOH (5mL) it is disposable add NaOH (5mL, 12.50mmol).At 80 DEG C, the reactant mixture is stirred 12 hours.Then, the solution is concentrated, and pH is neutralized to dense HCl =7.0, stir simultaneously.Then filter, and filter cake is washed with water (10mL).Filter cake is dried in a vacuum, white-yellowish solid is obtained 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- ethyl-pyrimidine -5- carboxylic acids (0.5g, 1.221mmol, yield 76%).TLC (DCM/MeOH=10:1,Rf 0.4):1H NMR(400MHz,CD3OD)δ8.8-8.77 (m, 1H), 8.76-8.72 (m, 1H), 8.14 (d, J=1.7Hz, 1H), 7.41 (d, J=8.6Hz, 2H), 6.91 (d, J= 8.6Hz, 2H), 5.39 (s, 2H), 4.17-4.13 (m, 2H), 3.78 (s, 3H), 3.16-3.11 (m, 2H), 1.43 (t, J= 7.0Hz, 3H), 1.34 (t, J=7.6Hz, 3H)；LCMS m/z 410.1(M+H).
Step 5：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- ethyl-pyrimidines -5- Base) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N2The 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - 4- ethyl-pyrimidine -5- carboxylic acids (150mg, 0.366mmol), 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline (88mg, 0.366mmol) and Et3Disposably add in solution of the N (55.6mg, 0.550mmol) in 1,4- dioxanes (10mL) Enter DPPA (121mg, 0.440mmol).At 80 DEG C, stirring reaction mixture 2 hours.Then, the solution is concentrated.By preparing TLC (DCM/MeOH=10:1,Rf=residue 0.5) is purified, obtain 1- (2- (5- ethyoxyls -6- ((the 4- first of white-yellowish solid Oxy-benzyl) epoxide) pyridin-3-yl) -4- ethyl-pyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoros Methyl) phenyl) urea (50mg, 0.077mmol, yield 21.07%).TLC (DCM/MeOH=10:1,Rf=0.4):1H NMR (400MHz,CD3OD) δ 9.07 (s, 1H), 8.74-8.72 (m, 1H), 8.12 (d, J=9.3Hz, 2H), 7.98 (br.s., 1H), 7.77-7.75 (m, 1H), 7.50 (br.s., 1H), 7.41 (d, J=8.6Hz, 2H), 7.35 (s, 1H), 6.92 (d, J= 8.8Hz, 2H), 5.40 (s, 2H), 4.17 (d, J=7.1Hz, 2H), 3.79 (s, 3H), 2.91 (d, J=7.5Hz, 2H), 2.26 (s, 3H), 1.42 (td, J=7.3,14.6Hz, 6H)；ES-LCMS m/z648.3(M+H).
Step 6：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- ethyl-pyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N21- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- of lower stirring Base) -4- ethyl-pyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea (50mg, The HCl (1mL, 4.00mmol) in MeOH 0.077mmol) is disposably added in the solution in DCM (5mL).At 20 DEG C, Stirring reaction mixture 1 hour.Then, concentrate solution.By preparing HPLC (instruments: DC/ posts：ASB C18150*25mm/ flow Dynamic phase A: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：25-55 (B%)) purifying remnants Thing, obtain the 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- ethyl-pyrimidine -5- bases) of white-yellowish solid - 3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea dihydrochloride (10.25mg, 0.017mmol, yield 21.67%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz,DMSO-d6)δ11.95-11.87(m,1H), 10.44 (br.s., 1H), 9.56 (br.s., 1H), 8.98 (d, J=3.4Hz, 1H), 8.10-7.87 (m, 4H), 7.74 (br.s.,1H),7.59(s,1H),5.73(s,1H),4.03-3.98(m,2H),2.85-2.80(m,2H),2.32(s,3H), 1.34 (t, J=6.8Hz, 3H), 1.25 (t, J=7.5Hz, 3H)；ES-LCMS m/z 528.2(M+H).
Embodiment 57：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
Step1：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N22- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- stirred under atmosphere Base) disposably add in the solution of -4- methylpyrimidine -5- carboxylic acids (0.2g, 0.506mmol) in 1,4- dioxanes (4mL) Et3N (0.106mL, 0.759mmol) and DPPA (0.167g, 0.607mmol).Stir the reactant mixture 15 minutes.It is mixed to this 3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) aniline (0.122g, 0.506mmol) is added in compound the 1 of 1mL, Solution in 4- dioxanes, and it is heated to 100 DEG C 2 hours.Solvent is removed on the rotary evaporator.By preparing TLC (DCM： MeOH=10:1, Rf=residue 0.5) is purified, obtain 1- (2- (5- ethyoxyls -6- ((the 4- methoxybenzyls of white-yellowish solid Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) benzene Base) urea (70mg, 0.110mmol, yield 21.84%)：1H NMR(400MHz,CD3OD)δ9.10(s,1H),8.66(s,1H), 8.22 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 7.39 (d, J=4.2Hz, 3H), 6.90 (d, J=8.6Hz, 2H), 5.37 (s, 2H), 4.19-4.13 (m, 2H), 3.78 (s, 3H), 2.59 (s, 3H), 2.29 (s, 3H), 1.43 (t, J=6.9Hz, 3H)；LCMS m/z 634.2(M+H).
Step 2：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N21- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- of lower stirring Base) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea (70mg, The HCl (0.5mL, 2.000mmol) in MeOH 0.110mmol) is disposably added in the solution in DCM (5mL).At 20 DEG C Under, stirring reaction mixture 1 hour.Then, concentrate solution.By preparing HPLC (instrument: DC；Post: Gemini:C18 150* 25mm*10ul；Mobile phase A: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/min/ run times：15min/ gradients Distribution description：18-48 (B%)) purifying residue, obtain 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydros of white-yellowish solid Pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl-1 H-imidazole-1-groups) -5- (trifluoromethyl) phenyl) urea two Hydrochloride (39.06mg, 0.065mmol, yield 58.5%).TLC (DCM/MeOH=10:1,Rf=0.4):1H NMR (400MHz,DMSO-d6)δ10.95(br.s.,1H),9.64(s,1H),9.27(s,1H),9.05(s,1H),8.07(s,1H), 8.02(s,1H),7.96(br.s.,1H),7.89(s,1H),7.74(s,1H),7.56(s,1H),4.02-3.97(m,2H), 2.52 (s, 3H), 2.33 (s, 3H), 1.33 (t, J=6.8Hz, 3H)；ES-LCMS m/z 514.1(M+H).
Embodiment 58：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step1：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- ((4- Methoxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N22- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- stirred under atmosphere Base) disposably add in the solution of -4- methylpyrimidine -5- carboxylic acids (0.2g, 0.506mmol) in 1,4- dioxanes (5mL) Et3N (0.106mL, 0.759mmol) and DPPA (0.167g, 0.607mmol).At room temperature, 30 points of the reactant mixture is stirred Clock.4- ((dimethylamino) methyl) -3- (trifluoromethyl) aniline (0.088g, 0.405mmol) is added into the mixture to exist Solution in the 1mL dioxane of Isosorbide-5-Nitrae-, and it is heated to 100 DEG C 3 hours.Solvent is removed, and by preparing TLC (DCM/MeOH= 10:1,Rf=residue 0.4) is purified, obtain 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) of light yellow solid Phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (110mg, 0.180mmol, yield 35.6%).1H NMR(400MHz,CD3OD) δ 8.67 (d, J=1.8Hz, 1H), 8.08 (d, J =1.8Hz, 1H), 7.97 (s, 1H), 7.67 (d, J=8.8Hz, 1H), 7.40 (d, J=8.6Hz, 2H), 7.24 (d, J= 7.2Hz, 2H), 6.91 (d, J=8.6Hz, 2H), 5.38 (s, 2H), 4.16 (q, J=7.1Hz, 2H), 4.08 (br.s., 2H), 3.78 (s, 3H), 2.57 (s, 3H), 2.44 (s, 6H), 1.29 (t, J=7.3Hz, 3H)；ES-LCMS m/z 611.1(M+H).
Step 2：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N2The 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) stirred under atmosphere - 3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (110mg, The HCl (0.5mL, 2.000mmol) in MeOH 0.180mmol) is disposably added in the solution in DCM (2mL).At 20 DEG C Under, stirring reaction mixture 1 hour.Then, concentrate solution.By prepare HPLC (post: ASB C18150*25mm/ mobile phase As: Water+0.1%HCl)/Mobile phase B: MeCN/ flow velocitys：25mL/min/ run times: 15min/ gradients distribution description：15-45 (B%) residue) is purified, 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- of yellow solid is obtained (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride (21.34mg, 0.037mmol, yield 20.5%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz,CD3OD)δ9.12(s, 1H), 8.12 (dd, J=2.1,5.4Hz, 2H), 7.90-7.83 (m, 2H), 7.70 (d, J=8.6Hz, 1H), 4.46 (s, 2H), 4.18-4.15 (m, 2H), 2.93 (s, 6H), 2.61 (s, 3H), 1.48 (t, J=6.9Hz, 3H)；ES-LCMS m/z 491.2(M +H)。
Embodiment 59：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) urea
Step 1：4,6- dimethyl -2- oxo -1,2,5,6- tetrahydropyrimidine -5- carboxylic acid, ethyl esters
In 350mL pressure flask, by ethyl 3-oxobutanoate (16.27g, 125mmol), acetaldehyde (5.51g, 125mmol), the mixture of urea (7.51g, 125mmol) and ice AcOH (1mL, 17.47mmol) in EtOH (35mL) is heated to 90 DEG C overnight.The mixture is diluted with water.Precipitation is collected by filtration, is washed with water and air-dries, the 4,6- of white solid are obtained Dimethyl -2- oxo -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid, ethyl esters (12g, 60.5mmol, yield 48.4%)：1H NMR (400MHz,DMSO-d6)δ8.95(br.s.,1H),7.18(br.s.,1H),4.13-3.95(m,3H),2.12(s,3H), 1.16 (t, J=7.0Hz, 3H), 1.06 (d, J=6.4Hz, 3H)；LCMS m/z 202.1(M+H).
Step 2：4,6- dimethyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters
To at 0 DEG C, in N24,6- dimethyl -2- oxygen is added portionwise in the nitric acid (12mL, 17.66mmol) of lower stirring Generation -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid, ethyl esters (3.5g, 17.66mmol).At 0 DEG C, 10 points of the reactant mixture is stirred Clock.In the frozen water that the reaction solution is poured into 60g, then extracted with EA.By the organic extract of merging salt water washing, warp Na2SO4It is dried, filtered and concentrated.Obtain 4,6- dimethyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (2.6g, 13.25mmol, yield 75%).TLC (PE/EA=5:1,Rf=0.6):1H NMR(400MHz,CDCl3)δ13.71-13.48 (m, 1H), 4.36 (q, J=7.1Hz, 2H), 2.56 (s, 6H), 1.38 (t, J=7.1Hz, 3H)；ES-LCMS m/z 197.1(M +H)。
Step 3：The chloro- 4,6- dimethyl pyrimidines -5- carboxylic acid, ethyl esters of 2-
To at 20 DEG C, in N2The POCl of lower stirring3(10.42mL, 122mmol) and DIEA's (33mL, 189mmol) is molten 4,6- dimethyl -2- oxo -1,2- dihydro-pyrimidin -5- carboxylic acid, ethyl esters (2.4g, 12.23mmol) are slowly added in liquid.80 At DEG C, the reactant mixture is stirred 2 hours.Then, the solution is concentrated, and is distributed in EA and the NaHCO of saturation3Between solution. By the organic extract of merging salt water washing, through Na2SO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA=10: 1) residue is purified.TLC (PE/EA=10 will be passed through:1,Rf=0.7) find that all fractions comprising product merge, and concentrate, Obtain the chloro- 4,6- dimethyl pyrimidines -5- carboxylic acid, ethyl esters of 2- (1.6g, 7.45mmol, yield 60.9%) of yellow oil：1H NMR(400MHz,CDCl3) δ 4.43 (q, J=6.8Hz, 2H), 2.54 (s, 6H), 1.40 (t, J=7.1Hz, 3H)；ES-LCMS m/z 215.2(M+H)。
Step 4：2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4,6- dimethyl pyrimidines -5- Carboxylic acid, ethyl ester
To at 20 DEG C, in N23- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- of lower stirring Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (2.51g, 6.52mmol), the chloro- 4,6- dimethyl pyrimidines -5- of 2- Carboxylic acid, ethyl ester (1.4g, 6.52mmol) and Cs2CO3(4.25g, 13.04mmol) is in 1,4- dioxanes (15mL) and water (5.00mL) In solution in disposable add PdCl2(dppf)(0.477g,0.652mmol).At 110 DEG C, the reaction vessel 2 is heated small When.Then, solution is concentrated, and distributed between EA and water.By the organic extract of merging salt water washing, through MgSO4It is dry It is dry, filter and concentrate.Pass through silica gel column chromatography TLC (PE/EA=10:1,5:1) residue is purified.TLC (PE/EA=will be passed through 2：1, Rf0.5) find that all fractions comprising product merge, and concentrate, obtain the 2- (5- ethyoxyls -6- of light yellow solid ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4,6- dimethyl pyrimidine -5- carboxylic acid, ethyl esters (1.7g, 3.89mmol, yield 59.6%)：1H NMR(400MHz,CDCl3)δ8.86-8.82(m,1H),8.08-8.04(m,1H),7.48-7.42(m,2H), 6.87 (d, J=8.6Hz, 2H), 5.49 (s, 2H), 4.43 (s, 2H), 4.23-4.15 (m, 2H), 3.79 (s, 3H), 2.58 (s, 6H), 1.52-1.45 (m, 3H), 1.41 (t, J=7.2Hz, 3H)；LCMS m/z 438.2(M+H).
Step 5：2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- carboxylic acids
To at 20 DEG C, in N2The 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - It is disposable in solution of the 4,6- dimethyl pyrimidine -5- carboxylic acid, ethyl esters (500mg, 1.143mmol) in THF (5mL) to add NaOH (2.5mL,6.25mmol).At 100 DEG C, stirring reaction mixture 12 hours.Then, the solution is concentrated, and with dense HCl With to pH=7.0, stir simultaneously.Then, filtering solution, and wash filter cake with water (10mL).Filter cake is dried in a vacuum, obtains 2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- carboxylic acids of white-yellowish solid (300mg, 1.037mmol, yield 91.0%).TLC (DCM/MeOH=10:1,Rf0.4):1H NMR(400MHz,CD3OD)δ 8.16 (d, J=2.0Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 4.18-4.12 (m, 2H), 2.59-2.56 (m, 6H), 1.47 (t, J=6.9Hz, 3H)；LCMS m/z 290.1(M+H).
Step 6：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) urea
To at 20 DEG C, in N22- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- diformazans of lower stirring Yl pyrimidines -5- carboxylic acids (150mg, 0.519mmol), 4- ((dimethylamino) methyl) -3- (trifluoromethyl) aniline (113mg, 0.519mmol) and Et3It is disposable in solution of the N (79mg, 0.778mmol) in 1,4- dioxanes (8mL) to add DPPA (171mg,0.622mmol).Reactant mixture is heated to 80 DEG C 2 hours.Then, concentrate solution.By preparing HPLC (instruments : DC/ posts：ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/min/ gradients point Cloth is described：15-55 (B%)) purifying residue, obtain 1- (4- ((dimethylamino) methyl) -3- (fluoroforms of yellow solid Base) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) urea disalt Hydrochlorate (14.17mg, 0.024mmol, yield 4.72%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz, CD3OD) δ 8.23 (d, J=2.2Hz, 1H), 8.10 (d, J=2.0Hz, 1H), 7.92 (d, J=2.0Hz, 1H), 7.87 (dd, J =2.0,8.4Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 4.46 (s, 2H), 4.18 (q, J=7.2Hz, 2H), 2.92 (s, 6H), 2.59 (s, 6H), 1.48 (t, J=7.0Hz, 3H)；ES-LCMS m/z 505.3(M+H).
Embodiment 60：1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step1：1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N2The 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) of lower stirring - It is disposable in solution of the 4- methylpyrimidine -5- carboxylic acids (100mg, 0.253mmol) in 1,4- dioxanes (5mL) to add Et3N (0.053mL, 0.379mmol) and DPPA (84mg, 0.303mmol).At room temperature, stirring reaction mixture 30 minutes.To this 4- chloro- 3- (trifluoromethyl) aniline (39.6mg, 0.202mmol) is added in mixture in 1mL 1,4- dioxanes (1mL) Solution.The reaction solution is heated to 100 DEG C 3 hours, stirred simultaneously.The solution is concentrated in a vacuum, and by preparing TLC (PE/EA=5:1,Rf=residue 0.6) is purified, obtain 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- of white-yellowish solid (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (70mg, 0.088mmol, yield 34.8%).1H NMR(400MHz,CD3OD)δ8.68(s,1H),8.49(s,1H),8.09(s,1H), 8.01-7.98(m,1H),7.65(s,1H),7.51-7.48(m,1H),7.41-7.38(m,2H),6.92-6.89(m,2H), 5.39(s,2H),4.16-4.13(m,2H),3.78(s,3H),2.57(s,3H),1.44-1.41(m,3H)；ES-LCMS m/z 588.0(M+H)。
Step 2：1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea
To at 20 DEG C, in N2Stirred under atmosphere 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (70mg, 0.088mmol) is at DCM (2mL) In solution in disposably add the HCl (0.5mL, 2.000mmol) in MeOH.At 20 DEG C, stirring reaction mixture 1 is small When.Then, concentrate solution.By preparing HPLC (post: ASB C18 150*25mm/ mobile phase As: water+0.1%HCl)/mobile phase B: MeCN/ flow velocity：25mL/min/ run times: 15min/ gradients distribution description：40-70 (B%)) purifying residue, obtain Huang 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- of color solid Methylpyrimidine -5- bases) urea hydrochloride (35.11mg, 0.069mmol, yield 78%).TLC (DCM/MeOH=5:1,Rf= 0.4).1H NMR(400MHz,CD3OD) δ 9.11 (s, 1H), 8.11 (d, J=2.2Hz, 1H), 8.03 (d, J=2.4Hz, 1H), 7.86 (d, J=2.0Hz, 1H), 7.64 (dd, J=2.4,8.8Hz, 1H), 7.52 (d, J=8.8Hz, 1H), 4.16 (q, J= 7.0Hz, 2H), 2.59 (s, 3H), 1.48 (t, J=7.1Hz, 3H)；ES-LCMS m/z 467.9(M+H).
Embodiment 61：2- (4- (3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides
Step 1：(((2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by 3- by 4- by 2- Pyridine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides
At 20 DEG C, in N22- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- of lower stirring Methylpyrimidine -5- carboxylic acids are (disposable in the solution in 0.2g, 0.506mmol) dioxanes (5mL) to add Et3N(0.106mL, 0.759mmol) with DPPA (0.167g, 0.607mmol).At room temperature, stirring reaction mixture 30 minutes.Into the mixture Add 1,4- bis- Evil of 2- (4- amino -2- (trifluoromethyl) the phenyl) -2- methyl propanamides (0.125g, 0.506mmol) in 1mL Solution in alkane.Reaction solution is heated to 100 DEG C 3 hours, stirred simultaneously.The solution is concentrated in a vacuum, and by preparing TLC (DCM/MeOH=10:1,Rf=residue 0.5) is purified, obtain the 2- (4- (3- (2- (4- ethyoxyls -6- of light yellow solid ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl Propionamide (25mg, 0.039mmol, yield 7.74%)：1H NMR(400MHz,CD3OD)δ9.17(s,1H),8.27(s,1H), 7.93-7.92(m,1H),7.77(s,1H),7.66(s,1H),7.40-7.37(m,2H),6.93-6.90(m,2H),6.48(s, 1H),5.31(s,2H),4.14-4.12(m,2H),3.77(s,3H),2.56(s,3H),1.61(s,6H),1.37-1.35(m, 3H)；ES-LCMS m/z 639.2(M+H).
Step 2：2- (4- (3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) Urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides
To at 20 DEG C, in N22- (4- (3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyrroles of lower stirring Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides (25mg, 0.039mmol) The HCl (0.5mL, 2.000mmol) in MeOH is disposably added in solution in DCM (3mL).At 20 DEG C, stirring is anti- Answer mixture 1 hour.Then, concentrate solution.By preparing HPLC (instruments: DC/ posts：ASB C18150*25mm/ mobile phase As: Water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：20-50 (B%)) purifying residue, obtain To the 2- (4- (3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) of white-yellowish solid Urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides hydrochloride (9.34mg, 0.017mmol, yield 43.0%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz,CD3OD)δ9.53(s,1H),8.40(s,1H),7.98(s,1H), 7.68 (s, 2H), 6.15 (s, 1H), 4.35 (q, J=6.9Hz, 2H), 2.76 (s, 3H), 1.62 (s, 6H), 1.48 (t, J= 7.1Hz,3H)ES-LCMS m/z 519.1(M+H)。
Embodiment 62：1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) - 3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
Step 1：The bromo- 2- isocyanatos -4- picolines of 5-
To at 20 DEG C, in N2The bromo- 4- picolines -2- amine (500mg, 2.67mmol) of 5- of lower stirring are at THF (6mL) In solution in disposable add triphosgene (278mg, 0.936mmol).At 60 DEG C, stirring reaction mixture 2 hours.Step 2：1- (the bromo- 4- picolines -2- bases of 5-) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene Base) urea
To at 40 DEG C, in N24- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) benzene of lower stirring Amine (453mg, 1.831mmol), DMAP (11.18mg, 0.092mmol) and Et3N (0.765mL, 5.49mmol) is at THF (8mL) In solution in disposable add the bromo- 2- isocyanatos -4- picolines (500mg, 1.831mmol) of 5-.At 40 DEG C, stirring Reactant mixture 1 hour.The solution is concentrated in a vacuum, and by preparing HPLC (MeCN/H2O is as eluent, acid bar Part) purifying residue, obtain yellow solid 1- (the bromo- 4- picolines -2- bases of 5-) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea (500mg, 0.880mmol, yield 48.1%)：1H NMR(400MHz, DMSO-d6) δ 9.92 (s, 1H), 9.38 (s, 1H), 8.32 (s, 1H), 7.91 (d, J=2.8Hz, 1H), 7.62 (s, 1H), 7.52-7.49 (m, 1H), 6.70 (d, J=8.8Hz, 1H), 4.73 (d, J=6.8Hz, 2H), 4.58 (d, J=7.2Hz, 2H), 2.31(s,3H),1.63(s,3H)；ES-LCMS m/z(M+H)459.8,461.9.
Step 3：1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -4- methyl-[3,3'- bipyridyls] -6- Base) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
To at 20 DEG C, in N23- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- of lower stirring Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (126mg, 0.326mmol), 1- (the bromo- 4- picolines -2- of 5- Base) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) ureas (150mg, 0.326mmol) and Cs2CO3It is disposable in the solution of (265mg, 0.815mmol) in DMF (12mL) to add PdCl2(dppf)(11.92mg, 0.016mmol).Reaction vessel is sealed, and 130 DEG C are heated to 30 minutes using initial 100W in CEM Discover. After cooling, reactant is concentrated in a vacuum, and pass through TLC (DCM:MeOH=10:1,Rf=residue 0.7) is purified, obtain The 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -4- methyl-[3,3'- bipyridyls] -6- bases) of white-yellowish solid - 3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (70mg, 0.068mmol, yield 20.85%)：1H NMR(400MHz,CDCl3) δ 8.13 (br, 1H), 8.02 (s, 1H), 7.79 (d, J=2.0Hz, 1H), 7.52- 7.59 (m, 2H), 7.41-7.39 (m, 2H), 6.92 (d, J=2.0Hz, 1H), 6.86-6.84 (m, 2H), 6.68 (s, 1H), 6.38 (d, J=9.2Hz, 1H), 5.39 (s, 2H), 4.92 (d, J=6.8Hz, 2H), 4.52 (d, J=7.2Hz, 2H), 4.06- 4.01 (m, 2H), 3.42 (s, 3H), 2.22 (s, 3H), 1.68 (s, 3H), 1.39 (t, J=7.0Hz, 3H)；ES-LCMS m/z 639.2(M+H)。
Step 4：1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea
At room temperature, to compound 1- (5'- ethyoxyls -6'- ((4- methoxy-benzyls) epoxide) -4- methyl-[3,3'- connection Pyridine] -6- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (70mg, The TFA (3mL, 4.46mmol) in DCM is added in 0.110mmol).At 20 DEG C, stirring reaction mixture 1 hour.Then, Solution is concentrated, and distributed in EA and the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, warp MgSO4It is dried, filtered and concentrated.By preparing HPLC (MeCN/H2O is used as eluent, alkalescence condition) purifying residue, obtain 1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- of white solid ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea (26mg, 0.049mmol, yield 44.8%). TLC (DCM/MeOH=10:1,Rf 0.3):1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.75-7.70(m,3H), 6.95 (s, 1H), 6.70-6.67 (m, 2H), 6.44 (d, J=8.8Hz, 1H), 4.98 (d, J=6.8Hz, 2H), 4.58 (d, J= 6.8Hz, 2H), 4.09-4.04 (m, 2H), 2.30 (s, 3H), 1.74 (s, 3H), 1.53 (t, J=7.2Hz, 3H)；ES-LCMS m/z 519.2(M+H)。
Embodiment 63：2- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides
Step 1：(((2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by 3- by 4- by 2- Pyridine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides
To at 20 DEG C, in N22- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- stirred under atmosphere Base) disposably add in the solution of -4- methylpyrimidine -5- carboxylic acids (0.2g, 0.506mmol) in 1,4- dioxanes (4mL) Et3N (0.106mL, 0.759mmol) and DPPA (0.167g, 0.607mmol).Stirring reaction mixture 15 minutes.To the mixing 1,4- of 2- (4- amino -2- (trifluoromethyl) the phenyl) -2- methyl propanamides (0.125g, 0.506mmol) in 1mL is added in thing Solution in dioxane, and it is heated to 100 DEG C 2 hours.Solvent is removed on the rotary evaporator.By preparing TLC (DCM: MeOH =10:1,Rf=residue 0.5) is purified, obtain 2- (4- (3- (2- (5- ethyoxyls -6- ((the 4- methoxybenzyls of yellow solid Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides (0.15g, 0.235mmol, yield 46.4%)：1H NMR(400MHz,CD3OD)δ9.05(s,1H)8.63(s,1H),8.00(s, 1H),7.63(s,1H),7.58-7.53(m,2H),7.42-7.40(m,2H),6.94-6.92(m,2H),5.38(s,2H), 4.15-4.11(m,2H),3.78(s,3H),2.50(s,3H),1.47(s,6H),1.35-1.33(m,3H)；LCMS m/z: 639.8(M+H)。
Step 2：2- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) Urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides
To at 20 DEG C, in N22- (4- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) oxygen stirred under atmosphere Base) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides (150mg, The HCl (0.5mL, 2.000mmol) in MeOH 0.235mmol) is disposably added in the solution in DCM (5mL).At 20 DEG C Under, stirring reaction mixture 1 hour.Then, concentrate solution.By preparing HPLC (instruments: DC/ posts: ASB C18 150* 25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：17-47 (B%)) Residue is purified, 2- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- of white-yellowish solid are obtained Methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides hydrochloride (69.57mg, 0.121mmol, production Rate 51.6%).TLC (DCM/MeOH=5:1,Rf=0.4):1H NMR(400MHz,CD3OD)δ9.26(s,1H),8.19(d,J =2.0Hz, 1H), 7.95 (s, 1H), 7.88 (d, J=2.0Hz, 1H), 7.67 (s, 2H), 4.19 (q, J=6.9Hz, 2H), 2.66 (s, 3H), 1.62 (s, 6H), 1.50 (t, J=6.9Hz, 3H)；ES-LCMS m/z 519.1(M+H).
Embodiment 64：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- Hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
Step 1：2- (fluoro- 4- isocyanatos (isocyanato) phenyl of 3-) -4,4,5,5- tetramethyl -1,3,2- dioxas Boron heterocycle pentane (dioxaborolane)
To the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline (450mg, Triphosgene (225mg, 0.759mmol) 1.898mmol) is added in the mixture in THF (10mL).At 60 DEG C, stirring should Mixture 1 hour.LCMS display reactions are completed.The mixture is concentrated, 2- (the fluoro- 4- isocyanatophenyls of 3-) -4,4 is obtained, 5,5- tetramethyl -1,3,2- dioxaborolans alkane (478mg, 1.733mmol, yield 91%).
Step 2：3- (4- (3- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) benzene Base) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls
To 2- (the fluoro- 4- isocyanatophenyls of 3-) -4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane Et is added in the mixture of (415mg, 1.578mmol) in THF (20mL)3N (0.440mL, 3.16mmol) and 3- (4- ammonia Base -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (456mg, 1.578mmol).At 60 DEG C, the mixing is stirred Thing 12 hours.LCMS display reactions are completed.The mixture is concentrated in a vacuum, and passes through post (PE/EA=3:1, Rf 0.2) it is pure Change residue, obtain 3- (4- (3- (the fluoro- 4- of 2- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) benzene Base) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (857mg, 1.341mmol, yield 85%).1H NMR(400MHz,CDCl3) 8.18 (d, J=8.0Hz, 1H), 7.67 (d, J=2.0Hz, 1H), 7.54 (d, J=4.4Hz, 1H), 7.48-7.45 (m, 1H), 7.20 (d, J=2.8Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 4.22-4.16 (m, 2H), 3.08 (s,2H),1.32(s,12H),1.29-1.25(m,3H)；1.23(s,6H),ES-LCMS m/z553.1(M+H).
Step 3：3- (4- (3- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) Urea groups) -2- (trifluoromethyl) phenyl) -2,2- dimethyl propylene acid esters
In N2Under, to 3- (4- (3- (the fluoro- 4- of 2- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) Phenyl) urea groups) -2- (trifluoromethyl) phenyl) -2,2- dimethyl propylenes acid esters (150mg, 0.272mmol) is in 1,4- dioxanes In mixture in (3mL) and water (1mL) add 5- bromo- 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyridine (100mg, 0.296mmol)、PdCl2(dppf) (19.87mg, 0.027mmol) and Cs2CO3(177mg,0.543mmol).In microwave irradiation Under, at 110 DEG C, stir the mixture 30 minutes.LCMS display reactions are completed.The mixture is filtered, in a vacuum concentration filter Liquid, and residue is purified by TLC, obtain 3- (4- (3- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -2- fluorophenyls) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (104mg, 0.133mmol, yield 49.1%).1H NMR(400MHz,CDCl3) 8.11-8.05 (m, 1H), 7.85 (d, J=6.4Hz, 2H), 7.65-7.60 (m, 1H), 7.37-7.34 (m, 4H), 7.17 (d, J=8.4Hz, 2H), 6.88-6.85 (m, 2H), 5.46 (s, 2H), 4.15-4.09 (m,4H),3.76(s,3H),3.05(s,2H),1.40-1.39(m,3H),1.38-1.37(m,3H),1.25(s,6H)；ES- LCMS m/z 564.2(M-PMB+H)。
Step 4：1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
In N2Under, to 3- (4- (3- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorobenzene Base) urea groups) -2- (trifluoromethyl) phenyl) -2,2- ethyl dimethyls (80mg, 0.117mmol) are in THF (10mL) LAH (4.44mg, 0.117mmol) is added in mixture.At 20 DEG C, in H2Under, stir the mixture 1 hour.LCMS is shown Reaction is completed.The mixture is concentrated in a vacuum, and passes through TLC (PE/EA=2：1, Rf 0.2) residue is purified, 1- is obtained (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- (3- hydroxyl -2,2- diformazans Base propyl group) -3- (trifluoromethyl) phenyl) urea (30mg, 0.042mmol, yield 35.8%).1H NMR(400MHz,CDCl3) 8.11-8.07 (m, 1H), 7.80 (d, J=2.0Hz, 1H), 7.56 (d, J=7.6Hz, 2H), 7.37-7.32 (m, 3H), 7.18- 7.14(m,2H),7.11-7.10(m,1H),6.99-6.77(m,2H),5.36(s,2H),4.07-4.02(m,2H),3.70(s, 3H), 3.66 (d, J=8.0Hz, 2H), 3.00 (s, 2H), 1.38-1.34 (m, 3H), 1.22 (s, 6H)；ES-LCMS m/z 522.0(M-PMB+H)。
Step 5：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- hydroxyls Base -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea
In N2Under, to 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea (30mg, 0.047mmol) is in MeOH (5mL) Pd/C (4.98mg, 0.047mmol) is added in mixture.At 20 DEG C, in H2Under, stir the mixture 1 hour.LCMS is shown Reaction is completed.The mixture is concentrated in a vacuum, and purifies residue by preparing HPLC, obtains 1- (4- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- hydroxyl -2,2- dimethyl propyls) -3- (trifluoromethyl) benzene Base) urea (2.79mg, 5.26 μm of ol, yield 11.24%)：1H NMR(400MHz,CD3OD)8.15-8.13(m,1H),7.84(d, J=2.0Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.39-7.35 (m, 3H), 7.32-7.25 (m, 2H), 4.14 (d, J= 7.2Hz, 2H), 3.34 (s, 2H), 2.76 (s, 2H), 1.48 (d, J=6.8Hz, 3H), 0.84 (s, 6H)；ES-LCMS m/z 522.2(M+H)。
Embodiment 65：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxos - 1,6- dihydropyridine -3- bases) phenyl) urea
Step 1：4- ((1- methyl isophthalic acid H- pyrazoles -4- bases) methyl) -3- (trifluoromethyl) aniline
Under microwave, by 5- bromopyridine -2- amine (2g, 11.56mmol), (4- nitrobenzophenones) boric acid (1.930g, 11.56mmol)、PdCl2(dppf)(0.423g,0.578mmol)、Cs2CO3(7.53g, 23.12mmol) is in 1,4- dioxanes Mixture in (30mL) and water (5mL) is heated to 100 DEG C 1 hour.Then, the mixture is concentrated, residue is obtained, is used DCM (20mL × 2) is extracted, through Na2SO4Dry, concentration obtains residue, purified via column chromatography, obtains 5- (4- nitrobenzene Base) pyridine -2- amine (1g, 4.65mmol, yield 40.2%)；ES-LCMS m/z216.1(M+1).
Step 2：5- (4- nitrobenzophenones) pyridine -2 (1H) -one
At 0 DEG C, to 5- (4- nitrobenzophenones) pyridine -2- amine (1g, 4.65mmol) in H2SO4(33.2mL,3.5M, NaNO is added in mixture in 116mmol)2(20.10mL,2M,40.2mmol)., will after the mixture is stirred 2 hours The mixture is poured into frozen water, and is extracted with DCM (200mL × 2), through Na2SO4Dry, concentration obtains 5- (4- nitrobenzene Base) pyridine -2 (1H) -one (800mg, 3.70mmol, yield 80%)：1H NMR(400MHz,CD3OD)δ8.30-8.27(dd,J =8.8,2.8Hz, 2H), 8.02 (dd, J=9.2,2.8Hz, 1H), 7.89 (m, 1H), 7.80-7.77 (m, 2H), 6.68-6.65 (m,1H)；ES-LCMS m/z 217.1(M+H).
Step 3：1- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) -3- (4- ((1- methyl isophthalic acid H- pyrazoles -4- bases) methyl) -3- (trifluoromethyl) phenyl) urea
To 4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) aniline (80mg, 0.278mmol) in THF Triphosgene (27.3mg, 0.092mmol) is added in mixture in (10mL), 70 DEG C are then heated the mixture to 30 minutes, The mixture is concentrated, 1- ethyls -4- (4- isocyanatos -2- (trifluoromethyl) benzyl) piperazine (84mg, 0.268mmol, production is obtained Rate 96%).
Step 4：5- (4- aminophenyls) pyridine -2 (1H) -one
In H2Under atmosphere, under 20psi stir 5- (4- nitrobenzophenones) pyridine -2 (1H) -one (800mg, 3.70mmol), Mixture of the nickel (21.72mg, 0.370mmol) in MeOH (20mL) is stayed overnight.Then, filter the mixture, and concentrate filtrate, Obtain 5- (4- aminophenyls) pyridine -2 (1H) -one (400mg, 2.148mmol, yield 58.1%)：1H NMR(400MHz, CD3OD) δ 7.88-7.85 (dd, J=8.8,2.8Hz, 1H), 7.58-7.57 (d, J=2.8Hz, 1H), 7.25 (d, J= 8.4Hz, 1H), 6.79-6.77 (d, J=2.0Hz, 1H), 6.62-6.59 (d, J=10.2Hz, 1H)；ES-LCMS m/z 187.1(M+H)。
Step 5：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1, 6- dihydropyridine -3- bases) phenyl) urea
Stir 5- (4- aminophenyls) pyridine -2- alcohol (50mg, 0.269mmol), 5- (4- aminophenyls) pyridine -2- alcohol (50mg,0.269mmol)、Et3Mixtures of the N (0.075mL, 0.537mmol) in THF (10mL) is stayed overnight.Then, concentration should Mixture, obtains residue, by preparing HPLC purifying, obtains 1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (fluoroforms Base) phenyl) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) urea dihydrochloride (119.55mg, 0.209mmol, production Rate 78%)：1H NMR(400MHz,CD3OD) δ 8.60 (dd, J=9.2,2.4Hz, 1H), 8.41-8.40 (d, J=2.0Hz, 1H), 8.17-8.16 (d, J=2.0Hz, 1H), 8.05-8.03 (m, 1H), 7.85-7.83 (m, 1H), 7.66 (s, 4H), 7.32- 7.29 (m, 1H), 4.64 (m, 2H), 3.88-3.70 (m, 8H), 3.40-3.34 (m, 2H), 1.43 (t, J=7.20Hz, 3H)； ES-LCMS m/z 500.1(M+H)。
Embodiment 66：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxymethyl) cyclopropyl) -3- (trifluoromethyl) phenyl) urea hydrochloride
Step1：1- (2- (trifluoromethyl) phenyl) cyclopropylniitrile
By 2- (2- (trifluoromethyl) phenyl) acetonitrile (7g, 37.8mmol), N- benzyls-N, N- diethyl ethane chlorination ammonium The solution of the bromo- 2- chloroethanes (8.13g, 56.7mmol) of (0.172g, 0.756mmol), 1- is heated to 50 DEG C.Then, at 50 DEG C Under, the NaOH (9.07g, 227mmol) in water (10mL) is added portionwise into said mixture, stirring at such a temperature is obtained Mixture 16 hours.The mixture is cooled to 25 DEG C, is poured into 150mL water, is extracted with DCM (150mL × 2).It will close And organic layer washed with salt solution (100mL), through anhydrous Na2SO4Dry, filter and concentrate under reduced pressure, obtain 1- (2- (trifluoros Methyl) phenyl) cyclopropylniitrile (8g, 36.0mmol, yield 95%)：1H NMR (400MHz, MeOD-d4) δ 7.76 (d, J= 7.7Hz, 1H), 7.66 (q, J=7.7Hz, 2H), 7.60-7.54 (m, 1H), 1.77-1.73 (m, 2H), 1.52-1.47 (m, 2H)；ES-LCMS m/z 212(M+1).
Step 2：1- (4- nitros -2- (trifluoromethyl) phenyl) cyclopropylniitrile
At 0 DEG C, to 1- (2- (trifluoromethyl) phenyl) cyclopropylniitrile (8.5g, 40.2mmol) in H2SO4It is molten in (40mL) Nitro peracid potassium (4.07g, 40.2mmol) is added portionwise in liquid, obtained mixture is stirred at such a temperature 20 minutes.Should Mixture is poured into 100mL ice/water, is extracted with DCM (100mL × 2).The organic layer of merging is washed with salt solution (50mL) Wash, through anhydrous Na2SO4Dry, filter and concentrate under reduced pressure, obtain 1- (4- nitros -2- (trifluoromethyl) phenyl) cyclopropylniitrile (9g, 26.0mmol, yield 64.6%)：1H NMR (400MHz, MeOD-d4) δ 8.57 (d, J=2.2Hz, 1H), 8.49 (dd, J =2.3,8.5Hz, 1H), 7.99 (d, J=8.6Hz, 1H), 1.89-1.82 (m, 2H), 1.63-1.57 (m, 2H).
Step 3：1- (4- nitros -2- (trifluoromethyl) phenyl) cyclopanecarboxaldehyde
At -78 DEG C, to 1- (4- nitros -2- (trifluoromethyl) phenyl) cyclopropylniitrile (8g, 31.2mmol) in DCM DIBAl-H is added portionwise in solution in (100mL), obtained mixture is stirred at such a temperature 2 hours.The mixture is inclined In the 2N HCl solutions for entering 50mL, extracted with DCM (150mL × 2).The organic layer of merging is washed with salt solution (50mL), through nothing Water Na2SO4Dry, filter simultaneously concentrate under reduced pressure, obtain 1- (4- nitros -2- (trifluoromethyl) phenyl) cyclopanecarboxaldehyde (8g, 24.69mmol, yield 79%)：1H NMR (400MHz, MeOD-d4) δ 8.85 (s, 1H), 8.54 (d, J=2.2Hz, 1H), 8.45 (dd, J=2.3,8.5Hz, 1H), 7.77 (d, J=8.6Hz, 1H), 1.84-1.77 (m, 2H), 1.65-1.56 (m, 2H)； ES-LCMS m/z 202(M+1)。
Step 4：1- (4- amino -2- (trifluoromethyl) phenyl) cyclopanecarboxaldehyde
At 25 DEG C, in H2Under atmosphere, stirring 1- (4- nitros -2- (trifluoromethyl) phenyl) cyclopanecarboxaldehyde (8g, 30.9mmol), mixtures of the Pd/C (3.28g, 30.9mmol) in MeOH (100mL) 2 hours.Then, the mixture is filtered, Filtrate is concentrated, and passes through silica gel column chromatography (20%EA:80%PE, 80g silicagel column) purifying.TLC (EA will be passed through:PE=1：2, Rf=0.5) find that all fractions comprising product merge, and concentrate, obtain the 1- (4- amino -2- (trifluoros of light yellow oil Methyl) phenyl) cyclopanecarboxaldehyde (3.5g, 12.22mmol, yield 39.6%)：1H NMR(400MHz,MeOD-d4)δ9.01 (s, 1H), 7.14 (d, J=8.4Hz, 1H), 7.02-6.96 (m, 1H), 6.82 (dd, J=2.1,8.3Hz, 1H), 1.58 (br.s., 2H), 1.38 (d, J=2.9Hz, 2H)；ES-LCMS m/z230(M+1).
Step 5：(1- (4- amino -2- (trifluoromethyl) phenyl) cyclopropyl) methanol
At 25 DEG C, to 1- (4- amino -2- (trifluoromethyl) phenyl) cyclopanecarboxaldehyde (4g, 17.45mmol) in MeOH NaBH is added portionwise in solution in (50mL)4(1.321g, 34.9mmol), stirs obtained mixture 2 small at such a temperature When.The mixture is concentrated, 20mL water is added, is extracted with DCM (50mL × 2).The organic layer of merging is washed with salt solution (50mL) Wash, through anhydrous Na2SO4Dry, filter and concentrate under reduced pressure, obtain (1- (4- amino -2- (trifluoromethyl) phenyl) cyclopropyl) Methanol (3.1g, 12.07mmol, yield 69.1%)：1H NMR (400MHz, MeOD-d4) δ 7.29 (d, J=8.4Hz, 1H), 6.93 (d, J=2.4Hz, 1H), 6.79 (dd, J=2.2,8.4Hz, 1H), 3.49 (br.s., 2H), 0.90-0.83 (m, 2H), 0.80-0.73(m,2H)；ES-LCMS m/z 232(M+1).
Step 6：4- (1- (((t-butyldimethylsilyl) epoxide) methyl) cyclopropyl) -3- (trifluoromethyl) aniline
At 25 DEG C, to (1- (4- amino -2- (trifluoromethyl) phenyl) cyclopropyl) methanol (2.1g, 9.08mmol), 1H- TBSCl (1.506g, 9.99mmol) is added in solution of the imidazoles (1.546g, 22.71mmol) in DCM (30mL).In the temperature Under degree, obtained mixture is stirred 2 hours.In the water that the mixture is poured into 50mL, extracted with DCM (50mL × 2).It will close And organic layer washed with salt solution (50mL), through anhydrous Na2SO4Dry, filter and concentrate under reduced pressure, obtain residue, pass through Silica gel column chromatography (20%EA:80%PE, 24g silicagel column) the purifying residue.TLC (EA: PE=1 will be passed through：2,Rf= 0.5) find that all fractions comprising product merge, and concentrate, obtain the 4- (1- (((fert-butyidimethylsilyls of light yellow oil Silicyl) epoxide) methyl) cyclopropyl) -3- (trifluoromethyl) aniline (2.5g, 6.51mmol, yield 71.7%)：1H NMR (400MHz, MeOD-d4) δ 7.41 (d, J=8.4Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 6.93 (dd, J=2.2, 8.4Hz,1H),3.72(br.s.,2H),1.02-0.99(m,2H),0.96(s,9H),0.89(s,2H),0.00(s,6H)；ES- LCMS m/z 346(M+1)。
Step 7:1- (4- (1- (((t-butyldimethylsilyl) epoxide) methyl) cyclopropyl) -3- (trifluoromethyl) Phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
At 25 DEG C, to 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Carboxylic acid (100mg, 0.253mmol), Et3In solution of the N (0.053mL, 0.379mmol) in 1,4- dioxanes (10mL) in batches DPPA (77mg, 0.278mmol) is added, at such a temperature, obtained mixture is stirred 20 minutes.Added into said mixture 4- (1- (((t-butyldimethylsilyl) epoxide) methyl) cyclopropyl) -3- (trifluoromethyl) aniline (96mg, 0.278mmol), and 100 DEG C are heated to 2 hours.In the water that the mixture is poured into 20mL, extracted with DCM (50mL × 2). By organic phase salt water washing, through Na2SO4It is dried, filtered and concentrated.By preparing TLC (DCM: MeOH=20:1,Rf=0.5) Residue is purified, 1- (4- (1- (((t-butyldimethylsilyl) epoxide) methyl) cyclopropyl) -3- of white solid are obtained (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) urea (50.0mg, 0.047mmol, yield 18.8%)：1H NMR(400MHz,MeOD-d4)δ9.16(s,1H),8.19(d,J =2.0Hz, 1H), 7.99 (d, J=2.0Hz, 2H), 7.68-7.64 (m, 1H), 7.54 (d, J=8.6Hz, 1H), 7.38 (d, J =8.6Hz, 2H), 7.00 (d, J=8.6Hz, 2H), 4.30-4.24 (m, 2H), 3.91-3.88 (m, 3H), 3.75 (br.s., 2H), 2.68 (s, 3H), 1.61 (t, J=7.1Hz, 3H), 0.95 (s, 9H), 0.00 (s, 6H)；ES-LCMS m/z 738(M+ 1)。
Step 8：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxymethyl) cyclopropyl) -3- (trifluoromethyl) phenyl) urea hydrochloride
Stir 1- (4- (1- (((t-butyldimethylsilyl) epoxide) methyl) cyclopropyl) -3- (three in TFA Methyl fluoride) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) Solution of the urea (50mg, 0.068mmol) in DCM (20%, 10mL) 30 minutes.Then, the solution is concentrated, and by preparing HPLC (instrument: DC/ posts: Gemini C18 150*25mm*10ul/ mobile phase As: water (water+0.1%HCl)/Mobile phase B: MeCN/ gradients: 30-60 (B%)/flow velocity：25mL/min/ run times: 15min) purifying residue, obtain the 1- of white solid (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxymethyl) rings Propyl group) -3- (trifluoromethyl) phenyl) urea hydrochloride (6.71mg, 0.012mmol, yield 18.2%)：1H NMR(400MHz, MeOD-d4) δ 9.09 (s, 1H), 8.10 (d, J=2.0Hz, 1H), 7.86 (d, J=2.2Hz, 2H), 7.60-7.52 (m, 2H), 4.16 (q, J=6.9Hz, 2H), 3.54 (br.s., 2H), 2.58 (s, 3H), 1.48 (t, J=6.9Hz, 3H), 0.94 (s, 2H), 0.87(br.s.,2H)；ES-LCMS m/z 504.1(M+H).
Embodiment 67：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea
Step1：1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea
At 25 DEG C, to 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Carboxylic acid (100mg, 0.253mmol), Et3In solution of the N (0.053mL, 0.379mmol) in 1,4- dioxanes (10mL) in batches DPPA (77mg, 0.278mmol) is added, at such a temperature, obtained mixture is stirred 20 minutes.By 3- (5- methyl isophthalic acids, 3,4- Oxadiazole -2- bases) -5- (trifluoromethyl) aniline (67.7mg, 0.278mmol) is added in said mixture, and it is heated to 100 DEG C 2 hours.In the water that the mixture is poured into 20mL, extracted with DCM (50mL × 2).By organic extract salt water washing, Through Na2SO4It is dried, filtered and concentrated.By preparing TLC (DCM：MeOH=20:1,Rf=residue 0.5) is purified, obtain white 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (3- of solid (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea (20mg, 0.031mmol, yield 12.4%)：1H NMR(400MHz,MeOD-d4)δ9.17(s,1H),8.39(s,1H),7.94-7.91(m,1H),7.79(s,1H),7.55(s, 1H), 7.26 (s, 2H), 6.88 (s, 2H), 5.97-5.94 (m, 1H), 5.29 (d, J=12.7Hz, 2H), 4.07 (d, J= 6.8Hz,3H),3.76(s,3H),2.64(s,3H),2.38(s,3H),1.37-1.33(m,3H)；ES-LCMS m/z 738(M+ 1).
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea
At 25 DEG C, in H2Under gas atmosphere, stirring 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine - 3- yls) -4- methylpyrimidine -5- bases) -3- (3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea (25mg, 0.039mmol), mixtures of the Pd/C (4.19mg, 0.039mmol) in MeOH (10mL) 2 hours.Then, filter The mixture, and filtrate is concentrated, residue is obtained, by preparing the HPLC (posts of instrument: Gilson 215/: Gemini C18 10u 150*25mm/ mobile phase As: water (0.01mol/L (NH4)HCO3)/Mobile phase B: MeCN (neutral)/gradient: 20-50 (B%)/ Flow velocity：25mL/min) purify, obtain 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) -3- (3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea (4.08mg, 7.64 μm of ol, yield 19.4%)：1H NMR(400MHz,DMSO-d6)δ11.44-11.33(m,1H),9.85(s,1H),8.93(s,1H),8.53(s, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 5.76 (s, 1H), 4.01 (q, J=6.8Hz, 2H), 2.58 (s, 3H), 2.44 (s, 3H), 1.25 (t, J=7.0Hz, 3H)；ES-LCMS m/z 515.8(M+H).
Embodiment 68：1- (3- (tert-butyl group) -1- phenyl -1H- pyrazoles -5- bases) -3- (4- (6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) phenyl) urea
Step 1：3- (4- isocyanatos -2- (trifluoromethyl) phenoxy group) -3- methy oxetanes
At 0 DEG C, to 3- (tert-butyl group) -1- phenyl -1H- pyrazoles -5- amine (100mg, 0.464mmol), NaHCO3 (195mg, 2.322mmol) is in DCM (10mL) and H2In mixture in O (10mL) add triphosgene (45.5mg, 0.153mmol).After the mixture is stirred 30 minutes, the mixture is extracted with DCM (20mL × 2), through Na2SO4Dry, Concentration, obtains 3- (tert-butyl group) -5- isocyanato -1- phenyl -1H- pyrazoles (40mg, 0.166mmol, yield 35.7%).
Step 2：1- (3- (tert-butyl group) -1- phenyl -1H- pyrazoles -5- bases) -3- (4- (6- oxo -1,6- dihydropyridines -3- Base) phenyl) urea
To 5- (4- aminophenyls) pyridine -2 (1H) -one (30.9mg, 0.166mmol) and 3- (tert-butyl group) -5- isocyanide acyls Base -1- phenyl -1H- pyrazoles (40mg, 0.166mmol) adds Et in the mixture in THF (15mL)3N(0.046mL, 0.332mmol).Then, the mixture is heated to 60 DEG C 60 minutes, then, concentrates the mixture, obtain residue, pass through HPLC purifying is prepared, 1- (3- (tert-butyl group) -1- phenyl -1H- pyrazoles -5- bases) -3- (4- (6- oxo -1,6- dihydro pyrroles are obtained Pyridine -3- bases) phenyl) urea (15.87mg, 0.037mmol, yield 22.4%)：1H NMR(400MHz,CD3OD)δ8.31-8.28 (dd, J=9.20,2.80Hz, 1H), 8.08-8.07 (d, J=2.80Hz, 1H), 7.75-7.73 (m, 3H), 7.70-7.68 (m, 2H),7.57(m,4H),7.02-7.00(m,1H),6.90(s,1H),1.45(s,9H)；.ES-LCMS m/z 428.2(M+H).
Embodiment 69：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((4- Ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
Step1：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) urea
To the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline (500mg, Triphosgene (219mg, 0.738mmol) 2.109mmol) is added in the solution in THF (50mL).At 70 DEG C, stirring is obtained Mixture.After 30 minutes, lcms analysis shows that initial substance disappears.Solvent is removed under vacuo, and obtaining 2-, (3- is fluoro- 4- isocyanatophenyls) -4,4,5,5- tetramethyl -1,3,2- dioxaborolans alkane (520mg, 1.977mmol, yield 94%).At 70 DEG C, to 4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) aniline (568mg, 1.977mmol), Et32- (3- are added in the solution of N (0.827mL, 5.93mmol) and DMAP (24.15mg, 0.198mmol) in THF (50mL) Fluoro- 4- isocyanatophenyls) -4,4,5,5- tetramethyl -1,3,2- dioxaborolans alkane (520mg, 1.977mmol). At 70 DEG C, obtained mixture is stirred.After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Will be residual Excess is dissolved in DCM (100mL), and uses H2O (30mL) and salt solution (30mL) washing.Through Na2SO4Organic layer is dried, is filtered and dense Contracting.Residue is purified by column chromatography (DCM/MeOH=20/1), 1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- are obtained (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) urea (0.67g, 0.851mmol, yield 43.0%)：1H NMR(400MHz,CD3OD)δ8.17-8.14(m,1H),7.86(s,1H), 7.69-7.67 (m, 1H), 7.60 (d, J=8.4Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.41 (d, J=11.2Hz, 1H), 4.59 (s, 2H), 3.60 (s, 2H), 2.52-2.47 (m, 8H), 1.33 (s, 12H), 1.10 (t, J=7.2Hz, 3H)；ES-LCMS m/z m/z 551.2(M+H)。
Step 2：1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
In N2Under atmosphere, at 110 DEG C, 1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) benzene is stirred Base) -3- (the fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) urea (0.67g, 1.217mmol), the bromo- 3- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (0.412g, 1.217mmol), PdCl2 (dppf)-DCM adducts (0.099g, 0.122mmol) and Cs2CO3(0.793g, 2.435mmol) is at 1,4- dioxanes (12mL) With the solutions overnight in water (4mL).After lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.By remnants Thing is dissolved in EA (120mL), and uses H2O (40mL) and salt solution (40mL) washing.Through Na2SO4Organic layer is dried, filters and concentrates. Residue is purified by silica gel column chromatography (DCM/MeOH=30/1 to 20/1).It will be found by TLC (DCM/MeOH=10/1) All fractions comprising product merge, and concentrate, and obtain the 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) of brown solid Epoxide) pyridin-3-yl) -2- fluorophenyls) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (0.53g, 0.638mmol, yield 52.4%)：1H NMR(400MHz,CD3OD)δ8.17(m,1H),7.91-7.89(m,2H), 7.68 (d, J=8.4Hz, 1H), 7.61 (m, 1H), 7.44-7.38 (m, 5H), 6.90 (d, J=8.8Hz, 1H), 5.35 (s, 2H), 4.17-4.11 (s, 2H), 3.70 (s, 3H), 3.67-3.65 (m, 2H), 2.53-2.44 (m, 8H), 1.41 (t, J= 7.0Hz,3H),1.12-1.08(m,3H)；ES-LCMS m/z 682.2(M+H).
Step 3：1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((4- second Base piperazine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea
At 25 DEG C, 1- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine -3- in HCl are stirred Base) -2- fluorophenyls) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea (0.53g, 0.777mmol) the solution in MeOH (10mLl).After lcms analysis shows that initial substance disappears.Remove under vacuo molten Agent, and by prepare HPLC purify residue, obtain yellow solid 1- (4- (5- ethyoxyl -6- oxos -1,6- dihydropyridine - 3- yls) -2- fluorophenyls) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea dihydrochloride (293.81mg, 0.459mmol, yield 59.0%)：1H NMR(400MHz,CD3OD) δ 8.18 (t, J=8.4Hz, 1H), 8.02 (s,1H),7.82(m,1H),7.73(m,1H),7.49-7.41(m,4H),4.24-4.18(m,4H),3.76-3.25(m,8H), 3.12 (m, 2H), 1.49 (t, J=7.0Hz, 3H), 1.37 (t, J=7.2Hz, 3H)；ES-LCMS m/z 562.1(M+H).
Embodiment 70：1- (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethoxies Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
Step 1：(2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl-propyls) t-butyl carbamate
To 2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile (2g, 8.76mmol) in MeOH (20mL) Boc is added in suspension2O (2.238mL, 9.64mmol) and Raney nickel (0.514g, 8.76mmol, in H2In O 50%).28 At DEG C, in H2The mixture is hydrogenated under atmosphere (15Psi) 16 hours.Then, solution is filtered, concentrates and distribute in EA and saturation NaHCO3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel Column chromatography (PE/EA=5:1, silica gel=3g) purifying residue.TLC (PE/EA=5 will be passed through:1,Rf=0.5) find comprising production All fractions of thing merge, and concentrate, and obtain (2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl-props of light yellow solid Base) t-butyl carbamate (2.1g, 6.09mmol, yield 69.5%)：1H NMR(400MHz,CDCl3)δ7.35-7.33(d,J =8.4Hz, 1H), 7.06 (d, J=2.8Hz, 1H), 6.79-6.77 (d, J=8.4Hz, 1H), 3.78 (br.s., 2H), 3.43- 3.42 (d, J=6.4Hz, 2H), 1.40 (s, 15H)；ES-LCMS m/z 355.1(M+23H).
Step 2：((((2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by 3- by 4- by 2- Pyridine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl-propyls) t-butyl carbamate
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (300mg, 0.759mmol) and (2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl-propyls) t-butyl carbamate Et is added in the solution of (252mg, 0.759mmol) in 1,4- dioxanes (10mL)3N (0.317mL, 2.276mmol) and DPPA(313mg,1.138mmol).At 70 DEG C, the mixture is stirred 12 hours.Then, the solution is concentrated, and is distributed in EA With the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.It is logical Cross preparation TLC (PE/EA=1：1,Rf=residue 0.5) is purified, obtain (2- (4- (3- (2- (the 5- ethoxies of light yellow solid Base -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) - 2- methyl-propyls) t-butyl carbamate (125mg, 0.138mmol, yield 18.19%)：1H NMR(400MHz,CD3OD)δ 9.12(s,1H),8.67(s,1H),8.10-8.06(m,1H),7.91(s,1H),7.64-7.58(m,2H),7.42-7.40(d, J=8.4Hz, 2H), 6.93-6.91 (d, J=8.4Hz, 2H), 5.38 (s, 2H), 4.19-4.14 (q, J=7.2Hz, 2H)), 3.79(s,3H),3.37(s.,2H),2.57(m,3H),1.52-1.26(m,18H)；ES-LCMS m/z 725.2(M+H).
Step 3：1- (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
To (2- (4- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines - 5- yls) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl-propyls) t-butyl carbamate (125mg, 0.172mmol) is in DCM TFA (6.64mL, 8.62mmol) (in DCM 10%) is added in suspension in (5mL).At 25 DEG C, the mixture 2 is stirred Hour.Then, the solution is concentrated, and distributed in EA and the NaHCO of saturation3Between solution.The organic extract of merging is used Salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing HPLC (instruments: DC/ posts：ASB C18 150*25mm/ flow Phase A: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：12-42 (B%)) purifying remnants Thing, obtains 1- (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- second of light yellow solid Epoxide -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride (70.82mg, 0.122mmol, Yield 70.6%).TLC (DCM/MeOH=10:1,Rf=0.4):1H NMR(400MHz,CD3OD)δ9.16(s,1H),8.15- (8.14 d, J=2.0Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=2.0Hz, 1H), 7.77-7.75 (m, 1H), 7.69-7.67 (m, 1H), 4.20-4.15 (q, J=7.2Hz, 2H), 3.33 (s, 2H), 2.63 (s, 3H), 1.58 (s, 6H), 1.52-1.48 (t, J=7.2Hz, 3H)；ES-LCMS m/z 505.2(M+H).
Embodiment 71：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea
Step 1：The chloro- 5- isocyanatos -4- methylpyrimidines of 2-
Three are added into suspension of the chloro- 4- methylpyrimidines -5- amine (150mg, 1.045mmol) of 2- in THF (10mL) Phosgene (140mg, 0.470mmol).At 60 DEG C, stirring mixture 1 hour.The mixture is cooled to room temperature.Then.Concentration Solution.Obtain the chloro- 5- isocyanatos -4- methylpyrimidines of 2- (170mg, 1.003mmol, yield 96%).TLC (PE/EA=5:1, Rf=0.5)；ES-LCMS m/z 202.0(M+MeOH+H).
Step 2：1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea
By 1- (4- amino -2- (trifluoromethyl) phenyl) suspension of the ethyl ketone (213mg, 1.048mmol) in THF (5mL) Liquid is added in solution of the chloro- 5- isocyanatos -4- methylpyrimidines (178mg, 1.048mmol) of 2- in THF (5mL).Add Et3N (0.365mL, 2.62mmol) and DMAP (12.81mg, 0.105mmol), and it is 10 small in the case where the mixture is placed in into 60 DEG C When.The mixture is cooled to room temperature.Then, solution is concentrated, and distributed in EA and the NaHCO of saturation3Between solution.It will close And organic extract salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing TLC (PE/EA=5:1, Rf= 0.6) residue is purified, obtaining the 1- (4- acetyl group -3- (trifluoromethyl) phenyl) of light yellow solid, (the chloro- 4- methyl of 2- is phonetic by -3- Pyridine -5- bases) urea (110mg, 0.295mmol, yield 28.1%)：1H NMR(400MHz,CD3OD) δ 9.06-9.05 (d, J= 6.0Hz,1H),7.98(s,1H),7.79-7.72(m,2H),2.68(s,3H),2.47(s,3H)；ES-LCMS m/z 373.0 (M+H)。
Step 3：1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) Epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (the chloro- 4- methylpyrimidines -5- bases of 2-) urea (110mg, 3- ethyoxyls -2- ((4- methoxy-benzyls) oxygen 0.295mmol) is added in the solution in DMF (2.4mL) and water (0.800mL) Base) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (114mg, 0.295mmol).Add Cs2CO3(240mg, 0.738mmol) and PdCl2(PPh3)2(20.71mg, 0.030mmol), and under microwave, by the mixture It is placed in 110 DEG C 15 minutes.The mixture is cooled to room temperature.Then, solution is concentrated, and distributed in EA and the NaHCO of saturation3 Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing TLC (DCM/ MeOH=10:1,Rf=0.5) purify residue, obtain the 1- (4- acetyl group -3- (trifluoromethyl) phenyl) of light yellow solid - 3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (120mg, 0.201mmol, yield 68.3%)：1H NMR(400MHz,CD3OD) δ 9.10 (s, 1H), 8.66 (d, J=1.6Hz, 1H), 8.07 (s, 1H), 7.98-7.96 (d, J=8.4Hz, 1H), 7.74-7.62 (m, 3H), 7.41-7.39 (d, J=8.4Hz, 1H), 6.91-6.89 (d, J=8.4Hz, 2H), 5.37 (s, 2H), 4.18-4.13 (q, J=6.8Hz, 2H), 3.78 (s, 3H), 2.59- 2.55 (m, 6H), 1.45-1.41 (t, J=6.8Hz, 3H)；ES-LCMS m/z 596.1(M+H).
Step 4：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea
At 0 DEG C, to 1- (4- acetyl group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxybenzyls Base) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) in solution of the urea (120mg, 0.201mmol) in THF (10mL) plus Enter MeMgBr (3.36mL, 10.07mmol).The mixture is placed at 0 DEG C 2 hours.Then, by the NH of solution saturation4Cl The aqueous solution is quenched, concentration, and distributes in EA and the NaHCO of saturation3Between solution.The organic extract of merging is washed with salt Wash, through MgSO4It is dried, filtered and concentrated.By preparing TLC (PE/EA=5:1,Rf=residue 0.6) is purified, obtain light yellow 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- of solid (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea (21mg, 0.029mmol, yield 14.48%)：1H NMR (400MHz,CD3OD) δ 9.09 (s, 1H), 8.66 (s, 1H), 8.08-8.07 (d, J=2.0Hz, 1H), 7.88 (s, 1H), 7.65 (s, 2H), 7.41-7.39 (d, J=8.8Hz, 2H), 6.92-6.89 (d, J=8.8Hz, 2H), 5.38 (s, 2H), 4.18-4.13 (q, J=6.8Hz, 2H), 3.78 (s, 3H), 2.57 (s, 3H), 1.59 (s 6H), 1.45-1.41 (m, J=6.8Hz, 3H)；ES- LCMS m/z 612.2(M+H)。
Step 5：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea
To 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) suspension of urea (21mg, 0.034mmol) in MeOH (10mL) Pd/C (3.65mg, 0.034mmol, 10%) is added in liquid.At 26 DEG C, in H2The mixture 2 is hydrogenated under atmosphere (15Psi) small When.Then, filtering solution and concentrate.By preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying residue, obtain To 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- of white solid (2- hydroxy propane -2- bases) -3- (trifluoromethyl) phenyl) urea (9.63mg, 0.020mmol, yield 57.1%).TLC(DCM/ MeOH=10:1,Rf=0.4):1H NMR(400MHz,DMSO-d6)δ9.42(br.s.,1H),8.98(s,1H),8.42 (br.s., 1H), 7.90-7.88 (dd, J=2.0,8.4Hz, 2H), 7.62-7.57 (m, 3H), 5.01 (s, 1H), 4.03-3.98 (q, J=6.8Hz, 2H), 2.45 (s, 3H), 1.49 (s, 6H), 1.35-1.32 (t, J=6.8Hz, 3H)；ES-LCMS m/z 492.1(M+H)。
Embodiment 72：1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea hydrochloride
Step 1：The fluoro- 4- of 2- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) aniline
To at 20 DEG C, in N2The bromo- 2- fluoroanilines (40g, 211mmol) of 4- of lower stirring, 4,4,4', 4', 5,5,5', 5'- prestoxs -2,2'- double (1,3,2- dioxaborolans alkane) (64.1g, 253mmol) and KOAc (41.3g, 421mmol) It is disposable in solution in 1,4- dioxanes (500mL) to add PdCl2(dppf)(7.70g,10.53mmol).At 100 DEG C Under, stirring reaction mixture 3 hours.The solution is concentrated in a vacuum, obtains the fluoro- 4- of 2- (4,4,5,5- tetramethyls -1,3,2- bis- Oxa- boron heterocycle pentane -2- bases) aniline (44g, 158mmol, yield 74.9%)：1H NMR(400MHz,CDCl3)δ7.46- 7.40 (m, 2H), 6.75-6.71 (m, 1H), 1.30 (s, J=3.6Hz, 12H)；ES-LCMS m/z238.1(M+H).
Step 2：4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines
To the bromo- 3- ethyoxyls -2- of 5- ((4- methoxy-benzyls) epoxide) pyridine (5g, 14.78mmol) in 1,4- dioxanes 5- bromo- 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) pyridine is added in mixture in (30mL) and water (10.0mL) (5g,14.78mmol)、Cs2CO3(9.63g, 29.6mmol) and PdCl2(dppf)(1.082g,1.478mmol).At 110 DEG C Under, in N2Lower stirring mixture 16 hours.Then, the reaction residue is filtered, and concentrates filtrate, passes through silica gel column chromatography (PE/EA=8/1) purify.TLC (PE/EA=8/1, R will be passed throughf=0.6) find that all fractions comprising product merge, and it is dense Contracting, obtain white solid 4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines (4g, 9.77mmol, yield 66.1%)：1H NMR(400MHz,CD3OD) δ 7.83 (d, J=2.0Hz, 1H), 7.40-7.37 (m, 2H), 7.34 (d, J=2.0Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.14 (m, 1H), 6.92-6.89 (m, 3H), 5.33 (s, 2H), 4.15-4.09 (m, 2H), 3.78 (s, 3H), 1.40 (t, J=7.2Hz, 3H)；ES-LCMS m/z 369.1(M+H).
Step 3：3- ethyoxyls -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- methoxy-benzyls) epoxide) pyridine
By 4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluoroanilines (193.76mg, 0.526mmol) suspension in THF (10mL) is added to triphosgene (70.2mg, 0.237mmol) in THF (10mL) In solution.The mixture is placed at 60 DEG C 5 minutes.The mixture is cooled to room temperature.Then, concentrate solution.Obtain 3- second Epoxide -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- methoxy-benzyls) epoxide) pyridine (195mg, 0.494mmol, yield 94%).TLC (PE/EA=5/1, Rf 0.5):ES-LCMS m/z 307.0(M-87H)。
Step 4：1- (3- nitros -5- (trifluoromethyl) phenyl) -1H-1,2,4- triazoles
Added into solution of fluoro- 3- nitros -5- (trifluoromethyl) benzene (1g, 4.78mmol) of 1- in DMF (15mL) 1H-, 2,4- triazole (0.396g, 5.74mmol).Add Cs2CO3(3.12g, 9.56mmol), and the mixture is placed in 80 DEG C Lower 8 hours.The mixture is cooled to room temperature.Then, solution is concentrated, and distributed in EA and the NaHCO of saturation3Solution it Between.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography (PE/EA= 5/1) residue is purified.TLC (PE/EA=1/1, R will be passed throughf=0.5) find that all fractions comprising product merge, and it is dense Contracting, obtains 1- (3- nitros -5- (trifluoromethyl) phenyl) -1H-1 of light yellow solid, 2,4- triazoles (690mg, 2.67mmol, Yield 55.9%)：1H NMR(400MHz,CD3OD)δ9.43(s,1H),9.01(s,1H),8.65(s,1H),8.55(s,1H), 8.26(s,1H)；ES-LCMS m/z 259.0(M+H).
Step 5：3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) aniline
To 1- (3- nitros -5- (trifluoromethyl) phenyl) -1H-1,2,4- triazoles (690mg, 2.67mmol) in MeOH Pd/C (284mg, 2.67mmol, 10%) is added in suspension in (10mL).At 26 DEG C, in H2Hydrogen under atmosphere (15Psi) Change the mixture 2 hours.Then, filter the solution and concentrate.Obtain the 3- (1H-1,2,4- triazol-1-yls) of white solid- 5- (trifluoromethyl) aniline (571mg, 2.502mmol, yield 94%).TLC (PE/EA=1/1, Rf=0.3):1H NMR (400MHz,CD3OD)δ9.06(s,1H),8.13(s,1H),7.26(s,2H),6.93(s,1H)；ES-LCMS m/z 229.1 (M+H)。
Step 6：1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) urea
To 3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) aniline (100mg, 0.438mmol) at THF (10mL) In suspension in add 3- ethyoxyls -5- (the fluoro- 4- isocyanatophenyls of 3-) -2- ((4- methoxy-benzyls) epoxide) pyridine (208mg,0.526mmol).Add Et3N (0.153mL, 1.096mmol) and DMAP (5.35mg, 0.044mmol), and will be mixed Compound is placed at 60 DEG C 10 hours.The mixture is cooled to room temperature.Then, solution is concentrated, and distributed in EA and saturation NaHCO3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing TLC (DCM/MeOH=20/1, Rf=0.4) purify residue, obtain light yellow solid 1- (3- (1H-1,2,4- triazol-1-yls)- 5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -2- fluorophenyls) urea (102mg, 0.164mmol, yield 37.4%)：ES-LCMS m/z623.1(M+H).
Step 7：1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea hydrochloride
To 1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyls -6- ((4- first Oxy-benzyl) epoxide) pyridin-3-yl) -2- fluorophenyls) in suspension of the urea (30mg, 0.048mmol) in MeOH (10mL) Add Pd/C (10.26mg, 0.096mmol, 10%).At 26 DEG C, in H2The mixture is hydrogenated under atmosphere (15Psi) 3 hours. Then, filtering solution and concentrate.By preparing HPLC (MeCN/H2O is used as eluent, acid condition) purifying, obtain yellow-white 1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- of solid Dihydropyridine -3- bases) -2- fluorophenyls) urea hydrochloride (16.88mg, 0.031mmol, yield 65.0%).TLC (DCM/MeOH= 10/1,Rf=0.4):1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.45(s,1H),8.92(s,1H),8.30(s, 1H), 8.22 (s, 1H), 8.12-8.07 (t, J=8.6Hz, 1H), 7.92-7.88 (d, J=7.8Hz, 1H), 7.59-7.55 (dd, J=12.8,2.0Hz, 1H), 7.42-7.40 (dd, J=8.8,2.0Hz, 1H), 7.33-7.32 (d, J=2.4Hz, 1H), 7.15-7.14 (d, J=2.4Hz, 1H), 4.09-4.04 (q, J=6.8Hz, 2H), 1.36-1.33 (t, J=6.8Hz, 3H)； ES-LCMS m/z 503.0(M+H)。
Embodiment 73：1- (4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
Step 1：(4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) t-butyl carbamate
To 2- (4- amino -2- (trifluoromethyl) phenyl) -2- methyl propionitrile (2g, 8.76mmol) in EtOH (20mL) Boc is added in suspension2O(3.05mL,13.15mmol).At 28 DEG C, the mixture is stirred 16 hours.Then, it is solution is dense Contracting, and distribute in EA and the NaHCO of saturation3Between solution.By the organic extract of merging salt water washing, through MgSO4Dry, Filter and concentrate.Pass through silica gel column chromatography (PE/EA=5:1, silica gel=3g) purifying residue.TLC (PE/EA=5 will be passed through: 1,Rf=0.6) find that all fractions comprising product merge, and concentrate, obtain (4- (2- dicyanopropanes-the 2- of light yellow solid Base) -3- (trifluoromethyl) phenyl) t-butyl carbamate (2.8g, 6.40mmol, yield 73.0%)：1H NMR(400MHz, CDCl3)δ7.76(s,1H),7.62(s,2H),1.85(s,6H),1.53(s,9H)；ES-LCMS m/z 329.1(M+H).
Step 2：(4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) t-butyl carbamate
To (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) t-butyl carbamate (3.18g, Raney nickel (1.137g, 19.37mmol, in H 9.69mmol) are added in the suspension in MeOH (20mL)2In O 50%) and NH4OH(10mL).At 28 DEG C, in 40psi H2Under atmosphere, the mixture is hydrogenated 12 hours.Then, the solution is filtered and dense Contracting, obtains residue.Obtain (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) t-butyl carbamate (1.5g, 4.39mmol, yield 45.3%).TLC (PE/EA=1：1,Rf=0.5):1H NMR(400MHz,CD3OD)δ7.92 (s, 1H), 7.67-7.65 (d, J=8.4Hz, 1H), 7.60-7.58 (d, J=8.8Hz, 1H), 3.17 (s, 2H), 1.57-1.43 (m,15H)；ES-LCMS m/z 333.1(M+H).
Step 3：(4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) carbamic acid uncle Butyl ester
To (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) t-butyl carbamate (1.5g, NaBH (OAc) 4.51mmol) is added in the suspension in MeOH (15mL)3(4.78g, 22.57mmol) and formaldehyde (0.249mL,9.03mmol).At 28 DEG C, the mixture is stirred 5 hours.Then, solution is concentrated, and distributes in EA and satisfy The NaHCO of sum3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silicon Glue column chromatography (PE/EA=1：1, silica gel=2g) purifying residue.TLC (PE/EA=1 will be passed through：1,Rf=0.5) find to include All fractions of product merge, and concentrate, and obtain (4- (1- (the dimethylamino) -2- methylpropanes -2- of light yellow solid Base) -3- (trifluoromethyl) phenyl) t-butyl carbamate (1.48g, 2.93mmol, yield 64.9%)：1H NMR(400MHz, CDCl3) δ 7.77 (s, 1H), 7.61-7.59 (d, J=8.8Hz, 1H), 7.50-7.48 (d, J=8.0Hz, 1H), 6.66 (s, 1H),2.75(s,2H),2.17(s,6H),1.53-1.51(m,15H)；ES-LCMS m/z 361.2(M+H).
Step 4：4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) aniline
TFA (0.633mL, 8.21mmol, 10%TFA, 10mL in DCM) is added to (4- (1- (dimethylamino)- 2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) t-butyl carbamate (1.48g, 4.11mmol) is in DCM (15mL) Solution in.The mixture is placed in 28 DEG C 4 hours.Then, concentrate solution, obtains residue.Pass through silica gel column chromatography (PE/ EA=1：1, silica gel=2g) purifying residue.TLC (PE/EA=1 will be passed through：1,Rf=0.4) find to include all levels of product Division simultaneously, and is concentrated, and obtains 4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) of light yellow solid Aniline (700mg, 2.313mmol, yield 56.3%)：1H NMR(400MHz,CDCl3) δ 7.44-7.42 (d, J=8.8Hz, 1H), 7.04 (s, 1H), 6.77 (dd, J=2.4,8.8Hz, 1H), 2.49 (s, 2H), 2.07 (s, 6H), 1.43 (s, 6H)；ES- LCMS m/z 261.1(M+H)。
Step 5：1- (4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (300mg, 0.759mmol) and 4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) aniline (197mg, 0.759mmol) Et is added in the solution in 1,4- dioxanes (10mL)3N (0.317mL, 2.276mmol) and DPPA (313mg,1.138mmol).At 70 DEG C, the mixture is stirred 12 hours.Then, solution is concentrated, and distributes in EA and satisfy The NaHCO of sum3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through system Standby TLC (DCM/MeOH=10:1, Rf=0.5) purify residue, obtain light yellow solid 1- (4- (1- (dimethylamino)- 2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridine - 3- yls) -4- methylpyrimidine -5- bases) urea (150mg, 0.129mmol, yield 16.96%)：1H NMR(400MHz,CD3OD)δ 8.69 (s, 1H), 7.38-7.35 (m, 2H), 7.27-7.19 (m, 3H), 7.07-7.03 (t, J=7.2Hz, 2H), 6.93-6.91 (d, J=8.4Hz, 2H), 5.39 (s, 2H), 4.20-4.14 (q, J=7.2Hz, 2H), 3.78 (s, 3H), 2.67-2.57 (m, 11H), 1.64 (s, 6H), 1.46-1.43 (t, J=7.2Hz, 3H)；ES-LCMS m/z 653.1(M+H).
Step 6：1- (4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
To 1- (4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- second Epoxide -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (150mg, 0.230mmol) exists Pd/C (24.46mg, 0.230mmol, 10%) is added in suspension in MeOH (10mL).At 26 DEG C, in H2Atmosphere The mixture is hydrogenated under (15Psi) 6 hours.Then, solution is filtered and concentrated, obtain residue.By preparing HPLC (instruments : DC/ posts：ASB C18 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/min/ gradients point Cloth is described：15-45 (B%)) purifying residue, obtain 1- (4- (1- (the dimethylamino) -2- methylpropanes -2- of yellow solid Base) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidines -5- Base) urea dihydrochloride (52.74mg, 0.086mmol, yield 37.6%).TLC (DCM/MeOH=10:1,Rf=0.4):1H NMR (400MHz,CD3OD) δ 9.22 (s, 1H), 8.18 (d, J=2.0Hz, 1H), 8.12-8.11 (d, J=2.0Hz, 1H), 7.89 (s, 1H), 7.79-7.74 (m, 2H), 4.22-4.16 (q, J=6.8Hz, 2H), 3.61 (s, 2H), 2.72 (s, 6H), 2.66 (s, 3H), 1.66 (s, 6H), 1.52-1.48 (t, J=6.8Hz, 3H)；ES-LCMS m/z 533.3(M+H).
Embodiment 74：1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethoxies Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
Step 1：N, N- dimethyl -2- (3- nitros -5- (trifluoromethyl) phenoxy group) ethamine
Added into suspension of fluoro- 3- nitros -5- (trifluoromethyl) benzene (2g, 9.56mmol) of 1- in DMF (10mL) 2- (dimethylamino) ethanol (2.56g, 28.7mmol) and K2CO3(2.64g,19.13mmol).At 80 DEG C, the mixing is stirred Thing 8 hours.The mixture is cooled to room temperature.Then, solution is concentrated, and distributed in EA and the NaHCO of saturation3Solution it Between.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.Pass through silica gel column chromatography TLC (10% EA:90%PE, 3g silicagel column) purifying residue.TLC (PE/EA=5 will be passed through:1, Rf=0.5) find owning comprising product Fraction merges, and obtains the N of light yellow solid, N- dimethyl -2- (3- nitros -5- (trifluoromethyl) phenoxy group) ethamine (1.35g, 4.85mmol, yield 50.7%)：1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.94(s,1H),7.51(s,1H), 4.20-4.17 (t, J=5.6Hz, 2H), 2.81-2.78 (t, J=5.6Hz, 2H), 2.36 (s, 6H)；ES-LCMS m/z 279.1(M+H)。
Step 2：3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) aniline
To N, N- dimethyl -2- (3- nitros -5- (trifluoromethyl) phenoxy group) ethamine (900mg, 3.23mmol) is in MeOH Pd/C (172mg, 0.162mmol) (10%) is added in suspension in (10mL).At 26 DEG C, in H2Under atmosphere (15Psi) Hydrogenate the mixture 3 hours.Then, filtering solution and concentrate.Obtain 3- (2- (dimethylamino) ethyoxyl) -5- (fluoroforms Base) aniline (600mg, 2.417mmol, yield 74.7%).TLC (PE/EA=1：1,Rf=0.4):1H NMR(400MHz, CDCl3) δ 6.58-6.51 (m, 2H), 6.38 (s, 1H), 4.06-4.03 (t, J=5.6Hz, 2H), 3.83 (br.s., 2H), 2.73-2.70 (t, J=5.6Hz, 2H), 2.34 (s, 6H)；ES-LCMS m/z 249.1(M+H).
Step 3：1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (200mg, 0.506mmol) and 3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) aniline (126mg, 0.506mmol) Et is added in solution in 1,4- dioxanes (10mL)3N (0.211mL, 1.517mmol) and DPPA (209mg, 0.759mmol).At 70 DEG C, the mixture is stirred 12 hours.Then, solution is concentrated, and distributed in EA and saturation NaHCO3Between solution.By the organic extract of merging salt water washing, through MgSO4It is dried, filtered and concentrated.By preparing TLC (PE/EA=1：1,Rf=residue 0.5) is purified, obtain 1- (3- (2- (dimethylamino) ethyoxyl) -5- of light yellow solid (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) urea (150mg, 0.234mmol, yield 46.3%)：1H NMR(400MHz,CD3OD) δ 9.12 (s, 1H), 8.67 (d, J= 1.8Hz, 1H), 8.08-8.07 (d, J=1.8Hz, 1H), 7.53 (s, 1H), 7.47-7.35 (m, 3H), 6.93-6.91 (d, J= 8.8Hz, 3H), 5.39 (s, 2H), 4.30-4.28 (t, J=5.2Hz, 2H), 4.19-4.14 (q, J=6.8Hz, 2H), 3.80 (s, 3H), 3.23-3.20 (m, 2H), 2.69 (s, 6H), 2.59 (s, 3H), 1.31 (t, J=7.2Hz, 3H)；ES-LCMS m/z 641.3(M+H)。
Step 4：1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
To 1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- ((4- Methoxy-benzyl) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (100mg, 0.156mmol) is in MeOH (10mL) Suspension in add Pd/C (16.61mg, 0.156mmol, 10%).At 25 DEG C, in H2This is hydrogenated under atmosphere (15Psi) to mix Compound 3 hours.Then, filtering solution and concentrate, obtain residue.By preparing HPLC (instruments: DC/ posts：ASB C18 150* 25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：23-53 (B%)) Residue is purified, 1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- of yellow solid are obtained (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride (25.02mg, 0.042mmol, yield 26.9%).TLC (DCM/MeOH=10:1,Rf=0.4):1H NMR(400MHz,CD3OD)δ9.26(s, 1H), 8.18 (d, J=2.0Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 7.49-7.47 (d, J=9.7Hz, 2H), 6.99 (s, 1H), 4.48-4.40 (m, 2H), 4.21-4.16 (q, J=6.8Hz, 2H), 3.71-3.59 (m, 2H), 3.02 (s, 6H), 2.69 (s, 3H), 1.51-1.48 (t, J=6.8Hz, 3H)；ES-LCMS m/z 521.2(M+H).
Following embodiments are prepared according to the method similar with those described above:
Embodiment 171：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - 3- (the fluoro- 4- of 2-
((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea
Step 1：2- (4- (4- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl Pyrimidine -5- bases) urea groups) -5- fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Triethylamine (0.184g, 1.821mmol), DPPA are added in the mixture of (0.4g, 0.910mmol) in toluene (50mL) (0.376g, 1.366mmol) and 2- (4- (4- amino-5-fluorines -2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate (0.473g,0.910mmol).At 120 DEG C, the mixture is stirred 12 hours.LCMS display reactions are completed.Concentrate the mixing Thing, obtains crude product, passes through post (DCM/MeOH=15:1, Rf=0.4) purify, obtain the 2- (4- (4- (3- of brown solid (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) the fluoro- 2- of -5- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate (340mg, 0.292mmol, yield 32.1%):1H NMR (METHANOL-d4, 400MHz) and δ 8.66 (s, 1H), 8.35 (d, J=7.5Hz, 1H), 7.58 (d, J=11.9Hz, 1H), 7.40 (d, J=7.5Hz, 4H), 6.90 (d, J=8.8Hz, 2H), 5.43 (s, 2H), 4.16-4.24 (m, 4H), 3.78 (s, 3H), 3.61(s,2H),2.50-2.61(m,10H),2.17(s,3H),2.04(s,3H),1.40-1.47(m,3H)；ES-LCMS m/z 756.2(M+H)。
Step 2：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea
To 2-, ((((2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl is phonetic by 3- by 4- by 4- Pyridine -5- bases) urea groups) -5- fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate (340mg, 0.292mmol) exists The NaOH (35.1mg, 0.877mmol) added in mixture in MeOH (10mL) in water (5mL).At 20 DEG C, stirring should Mixture 2 hours.LCMS display reactions are completed.The mixture is extracted with EtOAc (20mL × 3).By organic layer salt water washing, And concentrate, crude product is obtained, by preparing TLC (DCM:MeOH=10:1,Rf=0.4) purify, obtain the 1- of brown solid (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (fluoro- 4- ((4- of 2- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea (120mg, 0.101mmol, yield 34.5%)：1H NMR (400MHz, CHLOROFORM-d) δ 9.04 (s, 1H), 8.56 (d, J=7.5Hz, 2H), 7.48 (d, J=11.9Hz, 2H), 7.30 (br.s., 2H), 6.81 (d, J=8.4Hz, 2H), 5.41 (s, 2H), 4.13 (d, J=6.6Hz, 2H), 3.73 (s, 3H), 3.62 (d, J=5.3Hz, 4H), 2.67-2.61 (m, 10H), 2.17 (s, 3H), 1.41 (m, 3H)；ES-LCMS m/z 714.3(M+H)。
Step 3：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (2- Fluoro- 4- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea
To 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea (120mg, 0.101mmol) Hydrogen chloride, methanol (solvate) (0.252mL, 1.009mmol) are added in mixture in dichloromethane (DCM) (5mL). At 20 DEG C, the mixture is stirred 1 hour.LCMS display reactions are completed.The mixture is concentrated, crude product is obtained, by preparing HPLC (posts: ASB C18 150*25mm；Mobile phase A: water+0.1%HCl；Mobile phase B: MeCN；Flow velocity：25ml/ minutes；Gradient Distribution explanation: 17-37 (B%)) purifying, obtain in yellow solid 1- (2- (5- ethyoxyl -6- oxos -1,6- dihydropyridine - 3- yls) -4- methylpyrimidine -5- bases) -3- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) Phenyl) urea tri hydrochloride (18.5mg, 0.025mmol, yield 24.91%)：1H NMR(400MHz,METHANOL-d4)δ9.37 (s, 1H), 8.81 (d, J=7.5Hz, 1H), 8.24 (s, 1H), 7.93 (br.s., 2H), 4.38 (br.s., 2H), 4.21 (d, J =7.1Hz, 2H), 3.94-3.90 (m, 2H), 3.40 (d, J=4.4Hz, 10H), 2.70 (s, 3H), 1.51 (t, J=6.8Hz, 3H)；ES-LCMS m/z 594.4(M+H).
Embodiment 172：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- (2- hydroxyl-oxethyls) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：1- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- Methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea
At 20 DEG C, to 2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) - In mixture of the 4- methylpyrimidine -5- carboxylic acids (0.25g, 0.449mmol) in toluene (50mL) add triethylamine (0.091g, 0.897mmol), DPPA (0.185g, 0.673mmol) and 4- ((4- ethyl piperazidine -1- bases) methyl) fluoro- 5- (fluoroforms of -2- Base) aniline (0.152g, 0.449mmol).At 120 DEG C, the mixture is stirred 3 hours.The mixture is concentrated, is slightly produced Thing, passes through column chromatography (DCM/MeOH=20:1,Rf=0.4) purify, obtain the 1- (2- (5- (2- (benzyloxy) of brown solid Ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidines - 1- yls) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (205mg, 0.226mmol, yield 50.3%)：1H NMR (400MHz,METHANOL-d4) δ 9.21 (s, 1H), 8.63 (d, J=7.9Hz, 1H), 8.15 (d, J=1.8Hz, 1H), 7.42 (d, J=8.4Hz, 2H), 7.25 (d, J=7.5Hz, 7H), 6.89 (d, J=8.4Hz, 2H), 5.40 (s, 2H), 4.62 (s, 2H),4.34-4.27(m,2H),3.90-3.86(m,2H),3.78(s,3H),3.71(s,2H),3.20-3.07(m,10H), 2.58(s,3H),1.35-1.32(m,3H)；ES-LCMS m/z 804.2(M+H).
Step 2：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- (2- Hydroxyl-oxethyl) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
At 80 DEG C, 1- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridine -3- are stirred Base) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (100mg, 0.110mmol) is in hydrogen chloride, H2Mixture in O (1428 μ l, 11.01mmol) 1 hour.The mixture is concentrated, Crude product is obtained, by preparing HPLC (posts: ASB C18 150*25mm；Mobile phase A: water+0.1%HCl；Mobile phase B: MeCN； Flow velocity：25mLl/min；Gradient distribution explanation: 15-45 (B%)) purifying, obtain 1- (4- ((the 4- ethyl piperazines in yellow solid Piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3-2- (5- (2- hydroxyl-oxethyls) -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea tri hydrochloride (24.87mg, 0.035mmol, yield 32.1%).1H NMR (400MHz,METHANOL-d4) δ 9.25 (s, 1H), 8.69 (d, J=7.9Hz, 1H), 8.16 (d, J=2.2Hz, 1H), 7.90 (d, J=2.2Hz, 1H), 7.74 (d, J=11.9Hz, 1H), 4.13 (d, J=4.4Hz, 2H), 4.08-4.01 (m, 2H), 3.94 (br.s.,2H),3.66(br.s.,2H),3.48-3.33(m,4H),3.28-3.18(m,2H),3.01-2.77(m,2H), 2.62 (s, 3H), 1.38 (t, J=7.3Hz, 3H)；ES-LCMS m/z594.3(M+H).
Embodiment 173：1- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) benzene Base) -3- (2- (5- (2- hydroxyl-oxethyls) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：2- (4- (4- (3- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridine - 3- yls) -4- methylpyrimidine -5- bases) urea groups) -5- fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate
It is phonetic to 2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl In mixture of the pyridine -5- carboxylic acids (0.5g, 0.897mmol) in toluene (50mL) add triethylamine (0.182g, 1.795mmol), DPPA (0.370g, 1.346mmol) and 2- (4- (4- amino-5-fluorines -2- (trifluoromethyl) benzyl) piperazine -1- Base) ethylhexoate (0.435g, 0.897mmol).At 120 DEG C, the mixture is stirred 12 hours.The mixture is concentrated, is obtained To crude product, pass through post (DCM/MeOH=15:1,Rf=0.4) purify, obtain the 2- (4- (4- (3- (2- (5- of brown solid (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -5- Fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate (420mg, 0.341mmol, yield 38.0%)：1H NMR (400MHz,METHANOL-d4) δ 8.70 (d, J=1.8Hz, 1H), 8.36 (d, J=7.5Hz, 1H), 8.13 (s, 1H), 7.59 (d, J=11.9Hz, 1H), 7.41 (d, J=8.4Hz, 2H), 7.25-7.15 (m, 6H), 6.87 (d, J=8.4Hz, 2H), 5.39 (s,2H),4.61(s,2H),4.31-4.24(m,4H),3.87(br.s.,2H),3.77(s,3H),3.64(s,2H),2.87- 2.74(m,6H),2.61-2.57(m,4H),2.18(s,3H),2.05(s,3H)；ES-LCMS m/z862.2(M+H).
Step2：1- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- Methylpyrimidine -5- bases) -3- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea
To 2- (4- (4- (3- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea groups) -5- fluoro- 2- (trifluoromethyl) benzyl) piperazine -1- bases) ethylhexoate (420mg, The NaOH (40.9mg, 1.023mmol) in water (5mL) 0.341mmol) is added in the mixture in MeOH (10mL). At 20 DEG C, the mixture is stirred 2 hours.LCMS display reactions are completed.The mixture is extracted with EtOAc (20mL × 3).Will be organic Layer uses salt water washing, and concentrates, and obtains crude product, passes through TLC (DCM:MeOH=10:1,Rf=0.4) purify, obtain brown Solid 1- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines - 5- yls) -3- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea (110mg, 0.087mmol, yield 25.6%)：1H NMR(400MHz,CHLOROFORM-d)δ9.02(s,1H),8.68(s,1H),8.56 (d, J=7.5Hz, 2H), 8.28 (br.s., 1H), 8.01 (s, 1H), 7.50 (d, J=11.9Hz, 2H), 7.33-7.22 (m, 4H), 6.79 (d, J=8.4Hz, 2H), 5.39 (s, 2H), 4.57 (s, 2H), 4.24 (br.s., 2H), 3.82 (br.s., 2H), 3.73 (s, 3H), 3.57 (t, J=5.1Hz, 4H), 2.51-2.34 (m, 10H), 2.17 (s, 3H)；ES-LCMS m/z 820.2 (M+H)。
Step 3：1- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- (2- hydroxyl-oxethyls) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
At 80 DEG C, 1- (2- (5- (2- (benzyloxy) ethyoxyl) -6- ((4- methoxy-benzyls) epoxide) pyridine -3- are stirred Base) -4- methylpyrimidine -5- bases) -3- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) benzene Base) mixture of the urea (110mg, 0.087mmol) in hydrogen chloride solution (1.5mL, 18%) 1 hour.LCMS displays have been reacted Into.The mixture is concentrated, crude product is obtained, by preparing HPLC (posts: ASB C18 150*25mm；Mobile phase A: water+0.1% HCl；Mobile phase B: MeCN；Flow velocity：25mL/min；Gradient distribution description：10-40 (B%)) purifying, obtain in yellow solid 1- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- (2- hydroxyl second Epoxide) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea tri hydrochloride (32.5mg, 0.045mmol, Yield 51.8%)：1H NMR(400MHz,METHANOL-d4)δ9.31(s,1H),8.79-8.74(m,1H),8.22-8.19(m, 1H), 7.92 (d, J=1.8Hz, 1H), 7.89-7.84 (m, 1H), 4.33-4.27 (m, 2H), 4.14 (d, J=4.0Hz, 2H), 3.98-3.92(m,4H),3.67-3.34(m,10H),2.66(s,3H)；ES-LCMS m/z 610.3(M+H).
Embodiment 174：N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzsulfamide
Step 1：N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzsulfamide
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (1016mg, 2.57mmol), 3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl)-benzsulfamide (800mg, 2.57mmol) and Et3Nitrine phosphoric acid is added portionwise in the solution in 1,4- dioxanes (15ml) in N (0.716mL, 5.14mmol) Diphenyl ester (0.701mL, 3.08mmol).Then, in N2The mixture is stirred under atmosphere, and it is small at 80-90 DEG C to be heated to reflux 2 When.Lcms analysis shows that initial substance disappears.Solvent is removed under vacuo, residue is dissolved in DCM (60mL), and use H2O (20mL) and salt solution (20mL) are washed.By organic layer through Na2SO4It is dried, filtered and concentrated, obtains crude product, passes through silicagel column color Compose (DCM/MeOH=20:1 to 10:1) purify.TLC (DCM/MeOH=10 will be passed through:1,Rf=0.5) find comprising product All fractions merge, and concentrate, and obtain thick material.By preparing the HPLC (posts of instrument: Gilson 215/: Gemini C18 10u 150*25mm/ mobile phase As: 0.01mol/l NH3H are contained2O water/Mobile phase B: MeCN/ flow velocitys: 25mL/min/ gradients distribution Description：60-90 (B%)) crude product is further purified, obtain pure products N- (2- (dimethylamino) second of white solid Base) -3- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) - 5- (trifluoromethyl) benzsulfamide (170mg, 0.205mmol, yield 8.0%)：1H NMR(400MHz,CD3OD)δ9.10(s, 1H), 8.70 (d, J=2.0Hz, 1H), 8.26 (s, 1H), 8.12-8.06 (m, 2H), 7.76 (s, 1H), 7.42 (d, J= 9.0Hz, 2H), 6.92 (d, J=8.6Hz, 2H), 5.40 (s, 2H), 4.18 (q, J=7.0Hz, 2H), 3.80 (s, 3H), 3.04 (t, J=6.8Hz, 2H), 2.60 (s, 3H), 2.44 (t, J=6.8Hz, 2H), 2.21 (s, 6H), 1.45 (t, J=7.0Hz, 3H)；ES-LCMS m/z:584.2(M-PMB+H),704.2(M+H).
Step 2：N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzsulfamide
To N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzsulfamide (170mg, 0.242mmol) is in DCM 2,2,2- trifluoroacetic acids (1mL, 0.242mmol) are added in solution in (10mL).Then, at 25 DEG C, stir this and mix Compound 25 minutes.Reactant mixture is concentrated to dryness.Then, by preparing HPLC (instruments: AA/ posts：Gemini C18 10u 150*25mm/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：25mL/min；Gradient distribution explanation: 5-35 (B%) thick material) is purified, pure products N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethoxies in yellow solid are obtained Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzenesulfonamide, hydrochloride (98mg, 0.158mmol, yield 65.4%)：1H NMR(400MHz,DMSO)δ11.94(br.s.,1H),10.68(s,1H), 9.77(br.s.,1H),9.06(s,1H),9.02(s,1H),8.34(br.s.,1H),8.25(s,1H),8.13(s,1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.60 (d, J=2.0Hz, 1H), 4.03 (q, J=6.8Hz, 2H), 3.15 (br.s., 3H), 2.78 (d, J=4.8Hz, 4H), 2.53 (s, 6H), 1.36 (t, J=7.0Hz, 3H)；ES-LCMS m/z:584.2(M+H).
Embodiment 175：1- (4- (1- amino-ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：(1- (4- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl - Pyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) ethyl) t-butyl carbamate
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Et is added in the mixture of (100mg, 0.253mmol) in 1,4- dioxanes (15mL)3It is N (0.053mL, 0.379mmol), folded Nitrogen diphenyl phosphate (diphenyl phosphorazidate) (84mg, 0.303mmol), (1- (4- amino -2- (fluoroforms Base) phenyl) ethyl) t-butyl carbamate (92mg, 0.303mmol) and DMAP (3.09mg, 0.025mmol).At 80 DEG C, Stir the mixture 3 hours, then concentrate, and by preparing TLC (DCM/MeOH=20:1,Rf=0.6) purify, obtain yellow (1- (4- (the 3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) of solid Urea groups) -2- (trifluoromethyl) phenyl) ethyl) t-butyl carbamate (60mg, 0.073mmol, yield 28.9%)：1H NMR (400MHz,CD3OD) δ 9.13 (s, 1H), 8.71 (d, J=2.0Hz, 1H), 8.12 (d, J=1.6Hz, 1H), 7.84 (s., 1H), 7.70 (s., 1H), 7.61 (d, J=8.4Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 5.42 (s, 2H), 5.08-5.01 (m, 1H), 4.20 (q, J=7.2Hz, 2H), 3.82 (s, 3H), 2.61 (s, 3H), 1.47 (t, J =6.8Hz, 3H), 1.43 (s, 9H), 1.38 (d, J=7.2Hz, 3H)；ES-LCMS m/z 697.1(M+H).
Step 2：1- (4- (1- amino-ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To (1- (4- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide)-pyridin-3-yl) -4- methylpyrimidines - 5- yls) urea groups) -2- (trifluoromethyl) phenyl) ethyl) t-butyl carbamate (60mg, 0.086mmol) is in DCM (10mL) Solution in add TFA (1mL, 12.98mmol).At 25 DEG C, the mixture is stirred 2 hours.Reactant mixture is concentrated, and By preparing HPLC (posts: ASB C18 150*25mm；Mobile phase A: water+0.1%HCl；Mobile phase B: MeCN；Flow velocity：25mL/ min；Gradient distribution explanation: 10-40 (B%)) purifying, obtain 1- (4- (1- amino-ethyls) -3- (trifluoromethyl) of yellow solid Phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride (19.4mg, 0.035mmol, yield 41.0%)：1H NMR(400MHz,CD3OD) δ 9.22 (s, 1H), 8.18 (d, J=2.0Hz, 1H), 8.08 (d, J=2.0Hz, 1H), 7.92-7.84 (m, 2H), 7.76 (d, J=8.4Hz, 1H), 4.74 (q, J=6.8Hz, 1H), 4.20 (q, J=7.2Hz, 2H), 2.68 (s, 3H), 1.68 (d, J=7.2Hz, 3H), 1.52 (t, J=7.2Hz, 3H)； (M+H) .TLC of ES-LCMS m/z 477.0 (DCM/MeOH=8:1,Rf=0.2).
Embodiment 176：1- (4- (1- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step1：1- (4- (1- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 1- (4- (1- amino-ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) formic acid (5mL, 130mmol) is added in solution in urea (40mg, 0.084mmol) With formaldehyde (7mL, 94mmol).The mixture is reached environment temperature, and be heated to 70 DEG C.Reactant mixture is flowed back 3 hours. Then, the mixture is concentrated, and it is basified by adding excessive 50%NaOH.The mixture is concentrated, and by preparing HPLC (instruments: Gilson GX281；Post: Gemini 150*25mm*5um；Mobile phase A: water (0.05% ammonia spirit)；Flowing Phase B：Acetonitrile；Gradient: 30-60 (B%)；Flow velocity:25mL/ minutes；Run time: 10min) purifying, obtain the 1- of white solid (4- (1- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines - 3- yls) -4- methylpyrimidine -5- bases) urea (19.81mg, 0.039mmol, yield 45.9%), without being further purified.TLC (DCM/MeOH=10:1,Rf=0.2)：1H NMR(400MHz,CD3OD) δ 9.02 (s, 1H), 8.05 (d, J=2.4Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.84 (d, J=2.0Hz, 1H), 7.71-7.68 (m, 1H), 7.65-7.61 (m, 1H), 4.13 (q, J=6.8Hz, 2H), 3.51-3.45 (m, 1H), 2.54 (s, 3H), 2.21 (s, 6H), 1.47 (t, J=7.2Hz, 3H), 1.32 (d, J=6.4Hz, 3H)；ES-LCMS m/z 505.1(M+H).
Embodiment 177：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - 3- (4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) urea
Step1：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) urea
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (800mg, 2.023mmol), 4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) aniline (575mg, 2.226mmol) and Et3It is disposable in solution of the N (0.846mL, 6.07mmol) in 1,4- dioxanes (15mL) to add diphenyl phosphate azide (835mg,3.03mmol).Then, in N2The mixture is stirred under atmosphere, and is heated to 100 DEG C 3 hours.Lcms analysis is shown Initial substance disappears.Solvent is removed under vacuo.Residue is dissolved in DCM (60mL), and uses H2O (20mL) and salt solution (20mL) is washed.Through Na2SO4Organic layer is dried, filters and concentrates, obtain thick material, pass through silica gel column chromatography (DCM/MeOH= 20:1 to 5:1) purify, obtain the crude product 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) in dark yellow solid Pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) urea (300mg, 0.300mmol, yield 14.8%):1H NMR(400MHz,CD3OD) δ 9.02 (s, 1H), 8.06 (d, J=2.0Hz, 1H), 7.93 (d, J=2.0Hz, 1H), 7.84 (d, J=2.0Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.43 (d, J= 8.6Hz, 1H), 7.26 (d, J=7.0Hz, 2H), 7.21-7.19 (m, 2H), 4.14 (q, J=7.0Hz, 2H), 3.71 (br.s., 2H),3.42-3.36(m,4H),3.31(br.s.,3H),3.21-3.11(m,4H),2.53(s,3H),2.17(br.s.,2H), 2.08-1.98 (m, 2H), 1.48 (t, J=6.8Hz, 3H)；ES-LCMS:m/z 531.3(M-PMB+H),651.3(M+H).
Step 2：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) urea
To 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) urea (300mg, 0.461mmol) is at dichloromethane (18mL) In solution in be added dropwise TFA (2mL, 26.0mmol).At 20 DEG C, the mixture is stirred 1 hour.Lcms analysis shows starting material Matter disappears.Solvent is removed under vacuo.Then, by preparing the HPLC (posts of instrument: Gilson 215/: Gemini C18 10u 150*25mm/ mobile phase As: water (0.01mol/L NH3H2O)/Mobile phase B: MeCN/ flow velocitys：25mL/min；Gradient distribution explanation: 36-76 (B%)) purifying residue, obtain pure products 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydros in white-yellowish solid Pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- (2- (pyrrolidin-1-yl) ethyl) -3- (trifluoromethyl) phenyl) urea (35.6mg, 0.067mmol, yield 14.5%)：1H NMR(400MHz,CD3OD) δ 9.05 (s, 1H), 8.08 (d, J=2.0Hz, 1H), 7.90-7.84 (m, 2H), 7.62 (d, J=10.0Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 4.18-4.13 (m, 2H), 3.02-2.95 (m, 2H), 2.73 (d, J=9.0Hz, 2H), 2.67 (br.s., 4H), 2.56 (s, 3H), 1.87 (br.s., 4H), 1.49 (t, J=7.0Hz, 3H)；ES-LCMS:m/z 530.4.
Embodiment 178：1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethoxies Base -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride
Step 1：2- chlorine pyrimidine -5- amine
At 0 DEG C, to the chloro- 5- nitro-pyrimidines (5g, 31.3mmol) of 2- and zinc (20.49g, 313mmol) in methanol Ammonium chloride (16.77g, 313mmol) is added in solution in (150mL).At 25 DEG C, obtained mixture is stirred 16 hours. Lcms analysis shows that initial substance disappears.Filter the mixture.Filtrate is concentrated, crude product is obtained, passes through column chromatography (PE/EA= 3/1 to 1/1) purify.TLC (PE/EA=1/1, R will be passed throughf=0.5) find that all fractions comprising product merge, and concentrate, Obtain the 2- chlorine pyrimidine -5- amine (1g, 7.72mmol, yield 24.63%) of yellow solid：1H NMR(400MHz,METHANOL- d4)δ8.04(s,2H)；ES-LCMS m/z 130.1(M+H).
Step2：1- (2- chlorine pyrimidine -5- bases) -3- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl)-benzene Base) urea
Into solution of the 2- chlorine pyrimidine -5- amine (100mg, 0.772mmol) in THF (15mL) add triphosgene (80mg, 0.270mmol).At 60 DEG C, obtained mixture is stirred 0.5 hour.Lcms analysis shows that initial substance disappears.Under vacuo Solvent is removed, the chloro- 5- isocyanatos pyrimidines of 2- (120mg, 0.744mmol, yield 96%) of yellow oil are obtained.At 60 DEG C Under, to 3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) aniline (192mg, 0.771mmol) and Et3N Added in the solution of (0.323mL, 2.314mmol) in THF (15mL) 2- chloro- 5- isocyanatos pyrimidines (120mg, 0.771mmol) the solution in THF (15mL).At 60 DEG C, obtained mixture is stirred 1 hour.Remove under vacuo molten Agent.By residue distribution in DCM (30mL) and H2Between O (20mL), extracted with DCM (30mL × 2).By organic layer salt solution (20mL) is washed, through Na2SO4It is dried, filtered and concentrated, obtains 1- (2- chlorine pyrimidine -5- bases) -3- (3- (2- (two of yellow solid Methylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) urea (300mg, 0.743mmol, yield 96%)：1H NMR(400MHz, METHANOL-d4) δ 8.86 (s, 2H), 8.04 (s, 1H), 7.42 (s, 1H), 6.90 (s, 1H), 4.17 (t, J=5.3Hz, 2H), 4.08 (t, J=5.4Hz, 2H), 2.38 (s, 6H)；ES-LCMS m/z 404.2(M+H).
Step 3：1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea
In N2Under atmosphere, at 110 DEG C, 1- (2- chlorine pyrimidine -5- bases) -3- (3- (2- (dimethylamino) ethoxies are stirred Base) -5- (trifluoromethyl) phenyl) urea (150mg, 0.371mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (143mg, 0.371mmol), PdCl2(dppf) (27.2mg, 0.037mmol) and Cs2CO3The solution of (242mg, 0.743mmol) in 1,4- dioxanes (18mL) and water (6mL) 1 hour.Lcms analysis shows that initial substance disappears.Organic layer is separated and concentrated, crude product is obtained, by preparing TLC (DCM/ MeOH=10/1, Rf=0.2) purify, obtain 1- (3- (2- (dimethylamino) ethyoxyl) -5- (fluoroforms of yellow solid Base) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea (60mg, 0.091mmol, yield 24.5%)：1H NMR(400MHz,METHANOL-d4) δ 8.98 (s, 2H), 8.67 (d, J=1.8Hz, 1H), 8.08 (s, 1H), 7.60 (br.s., 1H), 7.41 (d, J=8.6Hz, 2H), 7.34 (brs, 1H), 6.96 (br s, 1H), 6.92 (d, J=8.8Hz, 2H), 5.40 (s, 2H), 4.37-4.30 (m, 2H), 4.27-4.21 (m, 3H), 4.17 (q, J= 7.0Hz, 2H), 3.79 (s, 3H), 2.77 (s, 6H), 1.45 (t, J=6.9Hz, 3H)；ES-LCMS m/z 627.3(M+H), 507.2(M+H-PMB)。
Step 4：1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride
At 25 DEG C, 1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- second is stirred Epoxide -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea (60mg, 0.096mmol) is in 2,2,2- trifluoros Solution in acetic acid, dichloromethane (solvate) (5mL, 3.72mmol) 0.5 hour.Lcms analysis shows that initial substance disappears Lose.Solvent is removed under vacuo.By preparing HPLC purification of crude product (instrument: DG/ posts：Phenomenex Synergi C18 150*30mm*4um/ mobile phase As: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys:25mL/ minutes/gradient distribution explanation: 18- 48 (B%)), obtain 1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- of yellow solid Ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride (20mg, 0.035mmol, yield 36.1%)：1H NMR(400MHz,METHANOL-d4) δ 8.96 (s, 2H), 8.11 (s, 1H), 7.92 (d, J=2.0Hz, 1H), 7.65(s,1H),7.35(s,1H),7.00(s,1H),4.45-4.41(m,2H),4.20-4.15(m,2H),3.66-3.62(m, 2H), 3.00 (s, 6H), 1.49 (t, J=6.9Hz, 3H)；ES-LCMS m/z507.3(M+H).
Embodiment 179：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea
Step1：1- (2- chlorine pyrimidine -5- bases) -3- (4- ((dimethylamino) methyl) -3- (trifluoromethyl)-phenyl)-urea
Triphosgene is added into solution of the 2- chlorine pyrimidine -5- amine (200mg, 1.544mmol) in THF (10mL) (151mg,0.509mmol).At 60 DEG C, the mixture is stirred 0.5 hour.The mixture is concentrated, is obtained in yellow solid Crude product (240mg), it is used in next step：ES-LCMS m/z 188.0(M+MeOH).To 4- ((dimethylamino) first Base) -3- (trifluoromethyl) aniline (337mg, 1.543mmol), triethylamine (156mg, 1.543mmol) is in THF (10mL) The chloro- 5- isocyanatos pyrimidines (240mg, 1.543mmol) of 2- are added in solution.At 60 DEG C, the mixture is stirred 0.5 hour. The mixture is concentrated, crude product is obtained, by preparing HPLC (posts: Phenomenex Synergi C18 250*21.2mm* 4um, condition 0.05%HCl-ACN Begin B 13 End B 43, the 100%B of gradient timetable (min) 10, retention time (min) 3, flow velocity (ml/min) 25) purifying, obtain product 1- (2- chlorine pyrimidine -5- bases) -3- (4- ((diformazans in yellow solid Base amino) methyl) -3- (trifluoromethyl) phenyl) urea dihydrochloride (90mg, 0.199mmol, yield 12.88%)：1HNMR (400MHz,METHANOL-d4) δ 8.87 (s, 2H), 8.06 (s, 1H), 7.91 (d, J=10.58Hz, 1H), 7.68 (d, J= 8.60Hz,1H),4.46(s,2H),2.93(s,6H)；ES-LCMS m/z:374.1(M+H)
Step 2：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- ((4- Methoxy-benzyl) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea
In microwave, at 110 DEG C, 1- (2- chlorine pyrimidine -5- bases) -3- (4- ((dimethylamino) methyl) -3- are stirred (trifluoromethyl)-phenyl) urea (50mg, 0.134mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5, 5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (51.5mg, 0.134mmol), Cs2CO3(43.6mg, 0.134mmol)、PdCl2(dppf) mixture of (9.79mg, 0.013mmol) in 1,4- dioxanes (3mL), water (1mL) 0.5 hour.Filter the mixture and concentrate, obtain crude product.By preparing TLC (DCM/MeOH=10:1,Rf=0.4) pure After change, product 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- in yellow solid are obtained Ethyoxyl -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea (75mg, 0.094mmol, yield 70.5%)：1H NMR(400MHz,METHANOL-d4) δ 8.98 (s, 2H), 8.66 (d, J=1.98Hz, 1H), 8.08 (d, J= 1.98Hz, 1H), 7.97 (s, 1H), 7.64-7.75 (m, 2H), 7.41 (d, J=8.60Hz, 2H), 6.92 (d, J=8.60Hz, 2H), 5.39 (s, 2H), 4.17 (q, J=6.98Hz, 2H), 3.79 (s, 3H), 2.66 (brs, 2H), 2.41 (s, 6H), 1.44 (t, J=6.95Hz, 3H)；ES-LCMS m/z:597.2(M+H)
Step 3：1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea
To 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxies Base benzyl) epoxide) pyridin-3-yl) pyrimidine -5- bases) TFA is added in solution of the urea (75mg, 0.094mmol) in DCM (5mL) (0.145mL,1.886mmol).At 22 DEG C, the mixture is stirred 0.5 hour.The mixture is concentrated, crude product is obtained, passed through Preparing HPLC, (post purifies Phenomenex Gemini 150*25mm*10um, condition：0.05%HCl-ACN Begin B 14 End B 44, the 100%B of gradient timetable (min) 12.2, retention time (min) 2.5, flow velocity (ml/min) 22) purifying, be in Product 1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen of yellow solid Generation -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride (17.06mg, 0.029mmol, yield 31.3%)：1H NMR(400MHz,METHANOL-d4) δ 8.93 (s, 2H) 8.07 (m, 2H) 7.86 (m, 2H) 7.69 (d, J=8.31Hz, 1H) 4.45 (s, 2H) 4.14 (q, J=6.85Hz, 2H), 2.92 (s, 6H) 1.47 (t, J=6.85Hz, 3H)；ES-LCMS m/z 477.2(M+H)
Embodiment 180：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) urea hydrochloride
Step1：1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5-carboxylic acid (300mg, 5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine 0.787mmol) is added in the solution in toluene (10mL) (153mg, 0.787mmol), diphenyl phosphate azide (325mg, 1.180mmol) and Et3N(0.219mL,1.573mmol). At 120 DEG C, the mixture is stirred 2 hours.The mixture is concentrated, crude product is obtained, by preparing TLC (DCM/MeOH=10:1, Rf=0.4) purify, obtain yellow product 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine - 5- yls) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea (50mg, 0.053mmol, yield 6.7%)：
1H NMR(400MHz,METHANOL-d4) δ 9.04 (s, 2H) 8.31 (s, 1H) 7.26 (d, J=7.28Hz, 2H) 7.19-7.22(m,2H)6.85(s,1H)6.48-6.52(m,1H)5.32(s,2H)4.12-4.18(m,2H)3.81(s,3H) 1.61(s,6H)1.36-1.39(m,3H)；ES-LCMS m/z 573.2(M+H).
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (1,1,1- Three fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) urea hydrochloride
To 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) in solution of the urea (50mg, 0.087mmol) in DCM (5mL) plus Enter TFA (0.067mL, 0.873mmol).At 15 DEG C, the mixture is stirred 1 hour.After being checked by LCMS, material quilt Exhaust.The mixture is concentrated, crude product is obtained, by preparing HPLC (post: Gemini 150*25 5u, condition 0.05%HCl- ACN Begin B 14 End B 44, gradient timetable (min) 100%B, retention time (minute), flow velocity (ml/min) 25) it is pure Change, obtain product 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- in yellow solid (5- (the fluoro- 2- methyl-propans -2- bases of 1,1,1- tri-) isoxazole -3-base) urea hydrochloride (10.38mg, 0.021mmol, yield 24.3%)：1H NMR(400MHz,METHANOL-d4)δ9.14(s,2H),8.17(s,1H),6.84(s,1H),6.22(s, 1H), 4.28 (q, 2H, J=7.6Hz), 1.61 (s, 6H), 1.45 (t, J=7.6Hz, 3H)；ES-LCMS m/z 453.1(M+ H)。
Embodiment 181：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) urea hydrochloride
Step1：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
At 23 DEG C, to 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5-carboxylic acid In the solution of (300mg, 0.787mmol) in 1,4- dioxanes (10mL) add diphenyl phosphate azide (260mg, 0.944mmol).The mixture is stirred 10 minutes, by Et3N (0.164mL, 1.180mmol) is added in said mixture.To 5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3- amine (153mg, 0.787mmol) is added in the mixture.23 At DEG C, the mixture is stirred 10 minutes, then at 100 DEG C, stir 1 hour.The mixture is concentrated, crude product is obtained, passed through Prepare TLC (DCM/MeOH=10:1,Rf=0.3) purify, obtain crude product 1- (2- (5- ethyoxyls -6- ((4- methoxybenzyls Base)-oxy) pyridin-3-yl) pyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea (100mg, 60% purity, 0.087mmol, yield 13.4%)：ES-LCMS m/z 573.0(M+H).
Step 2：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (1,1,1- Three fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) urea hydrochloride
To 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) urea (100mg, 60%, 0.105mmol) is molten in DCM (5mL) In liquid add TFA (2mL, in DCM 10%).At 23 DEG C, the mixture is stirred 0.5 hour.The mixture is concentrated, obtains thick Product, by prepare HPLC (Gilson GX281 posts: Gemini 150*25mm*5um mobile phase As: the water containing 0.1%HCl, Mobile phase B: MeCN, column temperature: 40 DEG C, gradient：30-60%B 10min, flow velocity: 25mL/min) purifying.It is in yellow solid to obtain Product 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (fluoro- 2- of 1,1,1- tri- Methylpropane -2- base) isoxazole -3-bases) urea hydrochloride 7.71mg, 0.015mmol, yield 14.3%)：1H NMR(400MHz, DMSO-d6) δ 8.83 (s, 2H) 7.94 (d, J=1.98Hz, 1H) 7.71 (d, J=2Hz, 1H) 6.76 (s, 1H) 4.03 (q, J= 7.2Hz, 2H), 1.49 (s, 6H) 1.36 (t, J=7.2Hz, 3H)；ES-LCMS m/z 453.0(M+H)
Embodiment 182：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (4- (2- methoxy ethoxies) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea.
At 25 DEG C, to 4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) aniline (79mg, 0.259mmol)、Et3N (0.098mL, 0.705mmol), 2- (6- ((4- methoxy-benzyls)-epoxide) -4- (2- methoxyl group ethoxies Base) pyridin-3-yl) add in the mixture of -4- methylpyrimidine -5- carboxylic acids (100mg, 0.235mmol) in toluene (40mL) Diphenyl phosphate azide (97mg, 0.353mmol).At 120 DEG C, the mixture is stirred 2 hours.This is quenched with water (20mL) anti- Should.Mixture is extracted with DCM (20ml × 3), organic extract is washed with salt solution (20mL), through Na2SO4Dry, filter and dense Contracting, obtain in crude yellow solid 1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) - 3- (2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (100mg, 0.110mmol, yield 46.8%)：1H NMR(400MHz,CD3OD) 9.32-9.25 (m, 1H), 8.60 (d, J= 7.5Hz, 1H), 8.31-8.23 (m, 1H), 7.61 (d, J=12.3Hz, 1H), 7.39 (d, J=8.4Hz, 2H), 6.94-6.88 (m,2H),6.53-6.49(m,1H),5.32(s,2H),4.24-4.17(m,2H),3.79(s,2H),3.73-3.70(m,2H), 3.63(s,2H),3.53(s,3H),3.33(s,3H),2.59(s,3H),2.56-2.42(m,8H),1.13-1.08(m,3H)； ES-LCMS m/z 698.3(M+H)。
Step 2：1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (4- (2- Methoxy ethoxy) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
To 1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (6- ((4- first Oxy-benzyl) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (100mg, 2,2,2- trifluoroacetic acids (66.6mg, 0.584mmol) 0.117mmol) are added in the solution in DCM (10mL), at 25 DEG C Stir the mixture 20 minutes.Solvent is removed under vacuo, by preparing HPLC (posts: Gemini 150*25 5u；Mobile phase B: 10mM NH4HCO3-ACN；Gradient: in 25 minutes, B is from 20 to 50；Flow velocity: 25mL/min；Wavelength: 220/254nm.) purifying, And freeze, obtain 1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- of white solid (2- (4- (2- methoxy ethoxies) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea (19.22mg, 0.032mmol, yield 27.1%)：1H NMR (400MHz, METHANOL-d4) 9.25 (s, 1H), 8.60 (d, J=7.5Hz, 1H), 7.80 (s, 1H), 7.61 (d, J=12.3Hz, 1H), 6.03 (s, 1H), 4.24-4.16 (m, 2H), 3.78-3.70 (m, 2H), 3.64 (s, 2H), 3.34 (s, 3H), 2.56 (s, 13H), 1.13 (t, J=7.3Hz, 3H)；ES-LCMS (m/z) (M+H)= 608.2。
Embodiment 183：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea tri hydrochloride
Step1：1- (2- chlorine pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) fluoro- 5- (fluoroforms of -2- Base) phenyl) urea
Into solution of the 2- chlorine pyrimidine -5- amine (100mg, 0.772mmol) in THF (15mL) add triphosgene (80mg, 0.270mmol).At 60 DEG C, obtained mixture is stirred 0.5 hour.Lcms analysis shows that initial substance disappears.Under vacuo Solvent is removed, the chloro- 5- isocyanatos pyrimidines of 2- (120mg, yield 95%) of yellow oil are obtained.At 60 DEG C, to 4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) aniline (236mg, 0.771mmol) and Et3N(0.323mL, The chloro- 5- isocyanatos pyrimidines (120mg, 0.771mmol) of 2- 2.314mmol) are added in the solution in THF (15mL) in THF Solution in (15mL).At 60 DEG C, obtained mixture is stirred 1 hour.Solvent is removed under vacuo.Residue distribution is existed DCM (30mL) and H2Between O (20mL), extracted with DCM (30mL × 2).Organic layer is washed with salt solution (20mL), through Na2SO4 It is dried, filtered and concentrated, obtains crude product, by prepares TLC (DCM/MeOH=10/1, Rf=0.4) purify, obtain brown and consolidate 1- (2- chlorine pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea of body (60mg, 0.111mmol, yield 14.34%)：1H NMR(400MHz,METHANOL-d4)δ8.89(s,2H),8.81(s,2H), 3.76 (s, 2H), 2.92-2.60 (m, 10H), 1.22 (t, J=7.4Hz, 3H)；ES-LCMS m/z 461.2(M+H).
Step 2：1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea
In N2Under atmosphere, at 110 DEG C, 1- (2- chlorine pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) first is stirred Base) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (59.8mg, 0.130mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) oxygen Base) -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (50mg, 0.130mmol), PdCl2 (dppf) (9.50mg, 0.013mmol) and Cs2CO3(85mg, 0.260mmol) is in 1,4- dioxanes (18mL) and water (6mL) Solution 1 hour.Lcms analysis shows that initial substance disappears.Separation organic layer is simultaneously concentrated, and crude product is obtained, by preparing TLC (DCM/MeOH=10/1, Rf=0.2) purify, obtain 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) oxygen of yellow solid Base) pyridin-3-yl) pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (60mg, 0.070mmol, yield 54.1%)：1H NMR(400MHz,METHANOL-d4) δ 8.97 (s, 2H), 8.58 (d, J= 7.6Hz, 1H), 8.09-8.07 (m, 1H), 7.62 (d, J=12.0Hz, 2H), 7.41 (d, J=8.8Hz, 2H), 6.92 (d, J= 8.4Hz, 2H), 5.39 (s, 2H), 4.17 (d, J=6.8Hz, 2H), 3.79 (s, 3H), 3.69-3.65 (m, 4H), 3.59 (s, 2H),3.57-3.53(m,4H),2.61(br.s.,2H),1.47-1.43(m,3H),1.28(m,3H)；ES-LCMS m/z 684.3(M+H),564.2(M+H-PMB)。
Step 3：1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (4- ((4- second Base piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea tri hydrochloride
At 25 DEG C, 1- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- are stirred Base) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (50mg, 0.073mmol) 2, Solution in 2,2- trifluoroacetic acids (in DCM 10%) (2mL, 1.488mmol) 0.5 hour.Lcms analysis shows initial substance Disappear.Solvent is removed under vacuo.By preparing HPLC (instruments: DB/ posts：Gemini 150*25 5u/ mobile phase As: water+ 0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：9-39 (B%)) purification of crude product, obtain Huang Color solid 1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidines - 1- yls) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea tri hydrochloride (5mg, 7.43 μm of ol, yield 10.2%)：1H NMR (400MHz,METHANOL-d4) δ 8.94 (s, 2H), 8.61 (d, J=7.2Hz, 1H), 8.07 (s, 1H), 7.87 (d, J= 2.0Hz, 1H), 7.67 (s, 1H), 4.16 (m, 2H), 3.80 (br.s., 2H), 3.69-3.65 (m, 2H), 3.56 (d, J= 4.8Hz, 2H), 3.25-3.20 (m, 2H), 3.13 (br.s., 2H), 2.55 (br.s., 2H), 1.49 (t, J=7.0Hz, 3H), 1.36 (t, J=7.2Hz, 3H)；ES-LCMS m/z 564.2(M+H).
Embodiment 184：1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl)-phenyl) -3- (2- (5- (2- methoxy ethoxies) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea tri hydrochloride
Step1：1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl) phenyl) -3- (2- (6- ((4- methoxy-benzyls) epoxide) -5- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
In N2Under atmosphere, at 120 DEG C, 2- (6- ((4- methoxy-benzyls) epoxide) -5- (2- methoxy ethoxies) are stirred Pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (100mg, 0.235mmol), the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) - 5- (trifluoromethyl) aniline (68.5mg, 0.235mmol), diphenyl phosphate azide (78mg, 0.282mmol) and Et3N The solution of (0.066mL, 0.470mmol) in toluene (5mL) 2 hours.Solvent is removed under vacuo.By preparing TLC (DCM/ MeOH=15/1, Rf=mixture 0.3) is purified, obtain 1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) first of yellow solid Base) -5- (trifluoromethyl) phenyl) -3- (2- (6- ((4- methoxy-benzyls) epoxide) -5- (2- methoxy ethoxies) pyridine -3- Base) -4- methylpyrimidine -5- bases) urea (53.3mg, 0.049mmol, yield 21%)：1H NMR(400MHz,METHANOL-d4) 9.20 (s, 1H), 8.69 (d, J=2.0Hz, 1H), 8.61 (d, J=7.6Hz, 1H), 8.12 (d, J=1.6Hz, 1H), 7.58 (d, J=12.0Hz, 1H), 7.40 (d, J=8.8Hz, 2H), 6.90 (d, J=8.4Hz, 2H), 5.39 (s, 2H), 4.24-4.22 (m,2H),3.82-3.76(m,7H),3.69(s,2H),3.41(s,3H),3.26(m,2H),3.11(m,4H),2.76(s, 3H),2.58(s,3H)；ES-LCMS m/z:714.2(M+H).
Step 2：1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- (2- Methoxy ethoxy) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea tri hydrochloride
At 25 DEG C, 1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl) phenyl) -3- is stirred (2- (6- ((4- methoxy-benzyls) epoxide) -5- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea The solution of (80mg, 0.112mmol) in TFA (in DCM 10%) (5mL) 0.5 hour.Lcms analysis shows that initial substance disappears Lose.Solvent is removed under vacuo.By preparing HPLC (posts: Phenomenex Synergi C18 250*21.2mm*4um/ streams Dynamic phase A: water+0.1%HCl/ Mobile phase Bs: MeCN/ flow velocitys：The distribution description of 25mL/min/ gradients：15-45 (B%)) purifying remnants Thing.After freeze, 1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (fluoroforms of yellow solid are obtained Base) phenyl) -3- (2- (5- (2- methoxy ethoxies) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) Urea tri hydrochloride (50mg, 0.070mmol, yield 62.5%)：1H NMR (400MHz, METHANOL-d4) d=9.25 (s, 1H), 8.68 (d, J=8.0Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.69 (d, J=12.0Hz, 1H), 4.26 (d, J= 4.5Hz,2H),3.94-3.82(m,4H),3.63-3.40(m,7H),3.15(br.s.,2H),2.96(s,3H),2.68(s, 2H),2.63(s,3H)；ES-LCMS m/z 594.2(M+H).
Embodiment 185：1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：(1- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4-
Methyl-pvrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methylpropane -2- bases) t-butyl carbamate
To 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (1- (4- amino -2- (trifluoromethyl) phenyl) -2- is added in the suspension of (500mg, 1.265mmol) in toluene (25mL) Methylpropane -2- bases) t-butyl carbamate (647mg, 1.265mmol), Et3N (0.264mL, 1.897mmol) and mazidox Diphenyl phthalate (522mg, 1.897mmol).At 130 DEG C, the mixture is stirred 12 hours.Then, the solution is concentrated, and is distributed Between ethyl acetate (15mL) and water (10mL).Organic extract is washed with salt solution (10mL), through Na2SO4Dry, filtering And concentrate.By preparing TLC (DCM/MeOH=10:1,Rf=thick material 0.4) is purified, obtain (1- (4- (the 3- of yellow solid (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) benzene Base) -2- methylpropane -2- bases)-t-butyl carbamate (124mg, 0.152mmol, yield 12.0%)：ES-LCMS m/z 605.4(M+H)。
Step 2：1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
At 16 DEG C, (1- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- in HCl are stirred Base) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methylpropane -2- bases) t-butyl carbamate The solution of (124mg, 0.152mmol) in EtOAc (10mL, 4N) 5 hours.Then, concentrate solution.By preparing HPLC (instrument Device: DB/ posts: Gemini 150*25mm*5um/ mobile phase As: water (0.05% ammonia spirit)/Mobile phase B：Acetonitrile/gradient: 25- 55 (B%)/flow velocitys: 25mL/min/ run times: 10min) purifying thick material, obtain 1- (4- (2- amino-2-methyls propyl group)- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea (31.8mg, 0.063mmol, yield 41.5%).TLC (DCM/MeOH=10:1,Rf=0.2):1H NMR(400MHz,CD3OD) δ 9.06 (s, 1H), 8.09 (d, J=2.0Hz, 1H), 7.90 (dd, J=2.0,15.1Hz, 2H), 7.65 (d, J=7.0Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 4.17 (q, J=6.9Hz, 2H), 2.94 (s, 2H), 2.58 (s, 3H), 1.51 (t, J= 7.0Hz,3H)；1.16(s,6H)；ES-LCMS m/z 505.2(M+H).
Embodiment 186：1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
Step 1：(1- (4- (3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methyl - Pyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methylpropane -2- bases) t-butyl carbamate
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids (1- (4- amino -2- (trifluoromethyl) phenyl) -2- is added in the suspension of (500mg, 1.265mmol) in toluene (15mL) Methylpropane -2- bases) t-butyl carbamate (647mg, 1.265mmol), Et3N (0.264mL, 1.897mmol) and mazidox Diphenyl phthalate (522mg, 1.897mmol).At 120 DEG C, the mixture is stirred 12 hours.Then, concentrate solution, and distribute Between ethyl acetate (20mL) and water (10mL).The organic extract of merging is washed with salt solution (10mL), through Na2SO4Dry, Filter and concentrate.By preparing TLC (DCM/MeOH=10:1, Rf=thick material 0.7) is purified, obtain (1- (the 4- of yellow solid (3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -2- (three Methyl fluoride) phenyl) -2- methylpropane -2- bases) t-butyl carbamate (300mg, 0.372mmol, yield 29.4%)：1H NMR(400MHz,CD3OD) δ 9.40-9.05 (m, 1H), 8.29 (s, 1H), 7.47-7.22 (m, 5H), 6.94 (d, J=8.5Hz, 2H), 6.50 (s, 1H), 5.33 (s, 2H), 4.16 (q, J=7.0Hz, 2H), 3.84-3.80 (m, 3H), 3.24-3.16 (m, 2H),2.66-2.54(m,3H),1.52(s,9H),1.42-1.35(m,3H),1.24-1.20(m,6H)；ES-LCMS m/z 725.4(M+H)。
Step 2：1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea
At 18 DEG C, 1- (4- (3- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyrroles in HCl are stirred Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methylpropane -2- bases) the tertiary fourth of carbamic acid Solution of the ester (300mg, 0.372mmol) in EtOAc (10mL, 4N, 40.0mmol) 10 hours.Then, the solution is concentrated.It is logical Cross preparation HPLC (instruments: DB/ posts：Gemini 150*25mm*5um/ mobile phase As: water (0.05% ammonia spirit)/Mobile phase B： Purify thick material, obtain the 1- of white solid acetonitrile/gradient: 23-53 (B%)/flow velocity: 25mL/min/ run times: 10min) (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines - 3- yls) -4- methylpyrimidine -5- bases) urea (56.88mg, 0.111mmol, yield 29.8%).TLC (DCM/MeOH=10:1,Rf =0.1):1H NMR(400MHz,CD3OD) δ 9.17 (s, 1H), 7.90 (d, J=2.2Hz, 1H), 7.78 (s, 1H), 7.69- 7.60 (m, 1H), 7.47 (d, J=8.4Hz, 1H), 6.00 (s, 1H), 4.12 (q, J=6.8Hz, 2H), 2.93 (s, 2H), 2.57 (s, 3H), 1.37 (t, J=7.1Hz, 3H), 1.14 (s, 6H)；ES-LCMS m/z 505.1(M+H).
Embodiment 187：N- (2- (dimethylamino) ethyl) -3- (3- (2- (4- (2- methoxy ethoxies) -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide
Step 1：N- (2- (dimethylamino) ethyl) -3- (3- (2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- first Epoxide ethyoxyl) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide
At 25 DEG C, to 3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzamide (100mg, 0.349mmol)、Et3N (0.133mL, 0.952mmol), 2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxyl group ethoxies Base) pyridin-3-yl) add in the mixture of -4- methylpyrimidine -5- carboxylic acids (150mg, 0.317mmol) in toluene (40mL) Diphenyl phosphate azide (131mg, 0.476mmol).At 120 DEG C, the mixture is stirred 2 hours.Solvent is removed in a vacuum, Residue is obtained, it is extracted with DCM (20mL × 2).Organic extract is washed with salt solution (20mL), through Na2SO4Dry, mistake Filter and concentrate, obtain crude product N- (2- (dimethylamino) ethyl) -3- (3- (2- (6- ((4- methoxybenzyls in yellow solid Base) epoxide) -4- (2- methoxy ethoxies) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzene first Acid amides (150mg, 0.129mmol, yield 40.7%)：1H NMR(400MHz,CD3OD)9.40(s,1H),8.27-8.18(m, 3H), 7.83 (br.s., 1H), 7.49 (br.s., 1H), 7.33 (br.s., 1H), 6.88 (d, J=8.8Hz, 2H), 6.13 (s, 1H),4.37-4.34(m,2H),3.78-3.75(m,3H),3.74-3.69(m,4H),3.42-3.38(m,3H),3.18-3.13 (m, 4H), 2.88 (s, 3H), 1.27 (t, J=7.3Hz, 6H)；ES-LCMS (m/z) (M+H)=698.4.
Step 2：N- (2- (dimethylamino) ethyl) -3- (3- (2- (4- (2- methoxy ethoxies) -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide
To N- (2- (dimethylamino) ethyl) -3- (3- (2- (6- ((4- methoxy-benzyls) epoxide) -4- (2- methoxyl groups Ethyoxyl) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide (150mg, 0.129mmol) 2,2,2- trifluoroacetic acids (73.5mg, 0.645mmol) are added in solution in dichloromethane (10mL).At 25 DEG C, stirring The mixture 20 minutes.Solvent is removed in a vacuum, by preparing HPLC (posts: Gemini 150*25 5u；Mobile phase: water (0.05% aqua ammonia v/v)-ACN；Gradient: B is from 14 to 44 in 10 minutes；Flow velocity: 25mL/min；Wavelength: 220/ 254nm) purify, and freeze, obtain N- (2- (dimethylamino) ethyl) -3- (3- (2- (4- (2- methoxyl groups of white solid Ethyoxyl) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide (45.4mg, 0.079mmol, yield 60.9%)：1H NMR(400MHz,CD3OD) 9.17 (s, 1H), 8.10 (d, J=13.2Hz, 2H), 7.81 (s, 2H), 6.04 (s, 1H), 4.21-4.18 (m, 2H), 3.75-3.72 (m, 2H), 3.55 (t, J=6.6Hz, 2H), 3.34 (s, 3H), 2.61 (t, J=6.6Hz, 2H), 2.57 (s, 3H), 2.34 (s, 6H)；ES-LCMS (m/z) (M+H)= 578.4。
Embodiment 188：
1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride
Step1：1- (2- chlorine pyrimidine -5- bases) -3- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) benzene Base) urea
Added into solution of the 2- chlorine pyrimidine -5- amine (150mg, 1.158mmol) in THF (20mL) double (trichloromethyls) Carbonic ester (0.082mL, 0.405mmol).At 65 DEG C, obtained mixture is stirred 0.5 hour.Lcms analysis shows starting material Matter disappears.Solvent is removed under vacuo, obtains the chloro- 5- isocyanatos pyrimidines of 2- (180mg, the 1.104mmol, production of yellow solid Rate 95%).At 60 DEG C, to 4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) aniline (273mg, 1.157mmol) and Et3The chloro- 5- isocyanatos of 2- are added in solution of the N (0.484mL, 3.47mmol) in THF (20mL) phonetic Solution of the pyridine (180mg, 1.157mmol) in THF (20mL).At 60 DEG C, obtained mixture is stirred 1 hour.In vacuum Lower removing solvent, obtains 1- (2- chlorine pyrimidine -5- bases) -3- (the fluoro- 5- (three of 4- ((dimethylamino) methyl) -2- of yellow solid Methyl fluoride) phenyl) urea (380mg, 0.165mmol, yield 14.2%)：1H NMR(400MHz,METHANOL-d4) d=8.85 (s, 2H), 7.61 (dd, J=4.9,9.0Hz, 1H), 7.33-7.28 (m, 1H), 3.70 (s, 2H), 2.30-2.28 (m, 6H)； ES-LCMS m/z 392.1(M+H)。
Step 2：1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea
In N2Under atmosphere, at 110 DEG C, 1- (2- chlorine pyrimidine -5- bases) -3- (4- ((dimethylamino) methyl) -2- are stirred Fluoro- 5- (trifluoromethyl) phenyl) urea (380mg, 0.165mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4, 4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) pyridine (63.5mg, 0.165mmol), PdCl2(dppf) (12.07mg, 0.016mmol) and Cs2CO3(107mg, 0.330mmol) is molten in 1,4- dioxanes (15mL) and water (5mL) Liquid 1 hour.Lcms analysis shows that initial substance disappears.Separate aqueous layer.Concentration of organic layers, obtains crude product, by preparing TLC (DCM/MeOH=15/1, Rf=0.3) purify, obtain 1- (the fluoro- 5- (three of 4- ((dimethylamino) methyl) -2- of brown solid Methyl fluoride) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea (60mg, 0.078mmol, yield 47.4%)：1H NMR(400MHz,DMSO-d6) d=8.98 (d, J=6.6Hz, 2H), 8.65- 8.61 (m, 1H), 8.50 (d, J=7.7Hz, 1H), 8.01 (br.s., 1H), 7.56 (d, J=12.3Hz, 1H), 7.40 (d, J= 8.6Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 5.35 (s, 2H), 4.13 (q, J=7.1Hz, 2H), 3.74 (s, 2H), 3.47 (s, 3H), 3.28 (s, 6H), 1.34 (t, J=6.7Hz, 3H)；ES-LCMS m/z 495.2(M+H-PMB).
Step 3：1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride
At 25 DEG C, 1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- are stirred Ethyoxyl -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea (50mg, 0.081mmol) is in 2,2,2- tri- Solution in fluoroacetic acid (in dichloromethane 10%) (2mL, 1.488mmol) 0.5 hour.Lcms analysis shows that initial substance disappears Lose.Solvent is removed under vacuo.By preparing HPLC (posts: Phenomenex Synergi C18 250*21.2mm*4um/ streams Dynamic phase A: water+0.05%HCl/ Mobile phase Bs: MeCN/ flow velocitys: 25mL/min/ gradients distribution description：22-52 (B%)) purifying is slightly Product, obtains 1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- second of yellow solid Epoxide -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) urea dihydrochloride (15mg, 0.026mmol, yield 31.6%)：1H NMR(400MHz,METHANOL-d4) δ 9.02 (s, 2H), 8.92 (d, J=7.2Hz, 1H), 8.11 (d, J= 1.2Hz, 1H), 7.86-7.82 (m, 2H), 4.53 (s, 2H), 4.22-4.17 (m, 2H), 2.97 (s, 6H), 1.53 (t, J= 6.6Hz,3H)；ES-LCMS m/z 495.3(M+H).
Embodiment 189：N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases)-pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide
Step 1：3- (3- (2- chlorine pyrimidine -5- bases) urea groups)-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzene Formamide
To the chloro- 5- isocyanatos pyrimidines (240mg, 0.984mmol) of 2- and Et3N (0.206mL, 1.477mmol) is in THF In solution in (10mL) add 3- amino-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzamide (271mg, 0.984mmol).At 60 DEG C, the mixture is stirred 0.5 hour.The mixture is concentrated, crude product is obtained, by preparing HPLC (post Phenomenex Gemini 150*25mm*10um conditions：0.225%FA-ACN Begin B 15End B 45, gradient The 100%B of time (min) 12.2, retention time (min) 2.5, flow velocity (ml/min) 22) purifying, obtain the production in yellow solid Thing 3- (3- (2- chlorine pyrimidine -5- bases) urea groups)-N- (2- (dimethylamino) ethyl) -5- (trifluoromethyl) benzamide (200mg, 0.413mmol, yield 42.0%)：1H NMR(400MHz,METHANOL-d4):δ8.88(s,2H)8.26(s,1H) 8.02 (s, 1H) 7.82 (s, 1H) 3.74 (t, J=5.77Hz, 2H) 3.27 (br.s., 2H) 2.90 (s, 6H)；ES-LCMS m/z: 431.1(M+H)。
Step 2：N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) oxygen Base)-pyridin-3-yl) pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide
Under nitrogen atmosphere, to 3- (3- (2- chlorine pyrimidine -5- bases) urea groups)-N- (2- (dimethylamino) ethyl) -5- (trifluoros Methyl) benzamide (100mg, 0.232mmol), 3- ethyoxyls -2- ((4- methoxy-benzyls) epoxide) -5- (4,4,5,5- tetra- Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) pyridine (89mg, 0.232mmol), Cs2CO3(76mg, 0.232mmol) exists PdCl is added in mixture in 1,4- dioxanes (6mL)/water (2.00mL)2(dppf)(170mg,0.232mmol).In microwave In, at 110 DEG C, stir the mixture 0.5 hour, then concentrate, obtain crude product, by preparing TLC (DCM/MeOH= 10:1,Rf=0.2) purify, obtain product N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethoxies in yellow solid Base -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide (60mg, 0.079mmol, yield 33.9%)：1H NMR(400MHz,METHANOL-d4)δ8.99(s,2H)8.65(s,1H)8.21 (br.s., 1H) 8.08 (d, J=12.96Hz, 2H) 7.82 (s, 1H) 7.41 (d, J=8.56Hz, 1H) 6.91 (d, J= 8.56Hz, 2H) 5.38 (s, 2H) 4.16 (q, J=7.01Hz, 2H) 3.79 (s, 3H) 3.73 (br.s., 2H) 3.19 (br.s., 2H) 2.81 (s, 6H) 1.44 (t, J=6.85Hz, 3H)；ES-LCMS m/z:654.2(M+H).
Step 3：N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base)-pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide
To N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls)-oxo) pyrroles Pyridine -3- bases) pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide (60mg, 0.092mmol) is molten in DCM (5mL) TFA (0.141mL, 1.836mmol) is added in liquid.At 25 DEG C, the mixture is stirred 1 hour.The mixture is concentrated, obtains thick Product, by preparing HPLC (post Phenomenex Synergi C18 250*21.2mm*4um, condition 0.05%HCl-ACN The End B 45 of Begin B 15, gradient timetable (min):10 100%B, retention time (min) 3, flow velocity (ml/min) 25) it is pure Change, obtain product N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxos -1,6- bis- in yellow solid Pyridinium hydroxide -3- bases) pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide dihydrochloride (7.77mg, 0.013mmol, production Rate 14.0%)：1H NMR(400MHz,DMSO-d6):δ11.93(brs,1H),9.83(s,1H),9.54(s,1H),8.91(s, 2H), 8.18 (s, 1H), 8.12 (s, 1H), 7.90 (brs., 1H), 7.85 (s, 1H), 7.58 (d, J=2.01Hz, 1H), 4.03 (q, J=7.19Hz, 2H), 3.63 (d, J=5.52Hz, 2H), 3.27 (brs, 2H), 2.84 (s, 6H), 1.36 (t, J= 6.90Hz,3H)；ES-LCMS m/z 534.1(M+H).
Embodiment 190：
1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos - 1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride
Step1：1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls - 6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea
In N2Under atmosphere, to 2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines - 5- carboxylic acids (200mg, 0.506mmol), diphenyl phosphate azide (209mg, 0.759mmol) and Et3N(0.106mL, Diphenyl phosphate azide (209mg, 0.759mmol) 0.759mmol) is added in the solution in 1,4- dioxanes (20mL). At 70 DEG C, obtained mixture is stirred 18 hours.Lcms analysis shows that initial substance disappears.Solvent is removed under vacuo.Pass through Prepare TLC (DCM/MeOH=10/1, Rf=residue 0.3) is purified, obtain 1- (4- ((dimethylamino) first of yellow solid Base) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- Methylpyrimidine -5- bases) urea (100mg, 0.151mmol, yield 29.9%)：1H NMR(400MHz,CD3OD)δ8.68(br.s., 1H), 8.09 (br.s., 1H), 7.41 (d, J=8.8Hz, 2H), 7.30 (s, 1H), 7.04 (br.s., 2H), 6.92 (d, J= 8.8Hz, 2H), 5.39 (s, 2H), 4.17 (d, J=6.8Hz, 2H), 3.83-3.74 (m, 5H), 2.59 (s, 3H), 2.31 (s, 6H), 1.44 (t, J=6.9Hz, 3H)；ES-LCMS m/z:629.2(M+H)；509.1(M+H-PMB).
Step 2：2- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls)-N- (3- (1- methyl Pyrrolidin-3-yl) -5- (trifluoromethyl) phenyl) acetamide
At 25 DEG C, 1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- are stirred Ethyoxyl -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) urea (100mg, 0.159mmol) exists Solution in 2,2,2- trifluoroacetic acids, dichloromethane (solvate) (3mL, 10%) 0.5 hour.Lcms analysis shows starting material Matter hour.Solvent is removed under vacuo.By preparing HPLC (posts: Gemini 150*25mm*5um/ mobile phase As: water+0.1% HCl/ Mobile phase Bs: MeCN/ flow velocitys：:The distribution description of 25mL/min/ gradients：5-35 (B%)) purification of crude product, obtain yellow and consolidate 1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- of body Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea dihydrochloride (40mg, 0.069mmol, yield 43.2%)：1H NMR (400MHz,CD3OD) δ 9.22-9.17 (m, 1H), 8.92 (d, J=7.6Hz, 1H), 8.12 (d, J=1.5Hz, 1H), 7.90 (d, J=2.0Hz, 1H), 7.68 (d, J=11.5Hz, 1H), 4.51 (s, 2H), 4.21-4.15 (m, 2H), 2.97 (s, 6H), 2.61 (s, 3H), 1.51 (t, J=7.0Hz, 3H)；ES-LCMS m/z:509.1(M+H).
Embodiment 191：
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- second Base piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea tri hydrochloride
Step1：1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidines -5- Base) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea
To 2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- carboxylic acids Triethylamine (92mg, 0.910mmol), DPPA are added in the mixture of (200mg, 0.455mmol) in toluene (30mL) (188mg, 0.683mmol) and 4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) aniline (164mg, 0.455mmol).At 120 DEG C, the mixture is stirred 12 hours.Solvent is removed under vacuo.Pass through column chromatography (DCM/MeOH =10/1, Rf=residue 0.4) is purified, obtain 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) oxygen of white-yellowish solid Base) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) fluoro- 5- of -2- (trifluoromethyl) Phenyl) urea (200mg, 0.172mmol, yield 37.8%)：1H NMR(400MHz,METHANOL-d4)δ9.25(s,1H), 8.67-8.61 (m, 2H), 8.27 (s, 1H), 7.60 (dd, J=5.7,12.3Hz, 2H), 7.46-7.37 (m, 2H), 7.34 (br.s.,1H),4.94(br.s.,2H),4.62(br.s.,2H),4.17-4.11(m,2H),3.70(br.s.,3H),3.20- 3.00(m,8H),2.65-2.53(m,5H),1.40-1.35(m,3H),1.31-1.28(m,3H)；ES-LCMS m/z 698.2 (M+H)。
Step 2：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea tri hydrochloride
To 1- (2- (4- ethyoxyls -6- ((4- methoxy-benzyls) epoxide) pyridin-3-yl) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea (200mg, 0.263mmol) is in dichloromethane TFA (10%, 2mL, 2.60mmol in DCM) is added in solution in alkane (3ml).At 25 DEG C, the mixture 1 is stirred small When.Solvent is removed under vacuo.By preparing HPLC (instruments: AA/ posts: Phenomenex Synergi C18 250* 21.2mm*4um/ mobile phase As: 0.05%HCl/ Mobile phase Bs: MeCN/ flow velocitys: 25ml/min/ run times: 10min/ gradients point Cloth is described：14-44 (B%)) purifying residue, and logical freeze-drying carrys out drying, obtains 1- (2- (the 4- ethoxies of white-yellowish solid Base -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- Fluoro- 5- (trifluoromethyl) phenyl) urea tri hydrochloride (70.1mg, 0.098mmol, yield 37.2%)：1H NMR(400MHz, METHANOL-d4) δ 9.64 (s, 1H), 8.79 (d, J=7.5Hz, 1H), 8.55 (s, 1H), 7.89 (d, J=11.9Hz, 1H), 6.22 (s, 1H), 4.41 (q, J=6.9Hz, 2H), 4.19 (brs, 2H), 3.70 (brs, 4H), 3.42 (dd, J=2.4, 6.8Hz, 2H), 3.20-2.97 (m, J=15.0Hz, 4H), 2.82 (s, 3H), 1.51 (t, J=6.8Hz, 3H), 1.38 (t, J= 7.1Hz,3H)；ES-LCMS m/z 578.2(M+H).
Embodiment 192：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - Crystal anhydrous free alkali (the compound A free alkalis of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea Anhydride)
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) suspension mistake of the urea (493.5mg) in 12.5mL acetone Night, while the temperature cycles between 40 DEG C to 5 DEG C.At 5 DEG C, the crystal seed of heating compound A free alkalis anhydride.By true Sky is separated by filtration solid, and is dried overnight in vacuum drying oven in 40 DEG C, obtains the title compound in crystalline solid.Work as exposure When 75%RH 5 days, free alkali anhydride is physically stable..
It is prepared by crystal seed:
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) suspension of urea in acetone 3 days, while in 40 DEG C and 5 DEG C Between temperature cycles.By isolated by vacuum filtration solid and drying, the title compound in crystalline solid is obtained.
X-ray powder diffraction (XRPD) pattern displaying of compound A free alkali anhydrides in Fig. 1, between the angle of diffraction and d- Away from general introduction be given in Table I below.XRPD analyses are in PANanalytical X ' Pert Pro Diffractometer diffraction Count in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator voltage: 45kV, generator electric current： 40mA, step-length: 0.02 ° of 2 θ, X'celeratorTMRTMS (Real Time Multi-Strip) detector.Incident beam side Set: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °) and 10mm light beam masks. The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slits.
Table I
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The Raman of compound A free alkali anhydrides Spectrum shows in fig. 2, it was observed that main peaks be located at 187.4,360.1,409.4,441.9,466.5,585.1,707.5, 742.7、772.7、790.0、850.8、904.4、950.3、1005.2、1247.3、1313.6、1329.7、1396.8、 1435.0、1468.6、1491.7、1530.2、1576.5、1622.9、1653.0、1710.0、2939.9cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and show in figure 3.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A dissociates The sharp endothermic peak of DSC thermal analysis curues display of alkali anhydride, with 251.95 DEG C of initial temperature, about 256.30 DEG C of peak temperature and 214.7J/g enthalpy.Skilled artisan recognize that initial temperature, peak temperature and the enthalpy of heat absorption may be according to experiment bars Part and change.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and show in Fig. 4.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A free alkali anhydrides are shown in 25 DEG C to 150 DEG C of temperature range Insignificant weight loss and 243.34 DEG C of thermal decomposition initial temperature.
Embodiment 193：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - First crystalline hydrate (the compound A of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Free alkali hydrate 1)
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) suspension of the urea in water 3 days, while 40 DEG C and 5 DEG C it Between temperature cycles.By isolated by vacuum filtration solid, air-dry 1 hour, be then in 40 DEG C of dryings in vacuum drying oven The title compound of crystalline solid.
X-ray powder diffraction (XRPD) pattern displaying of compound A free alkalis hydrate 1 in Figure 5, between the angle of diffraction and d- Away from general introduction be given in Table II below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer Diffractometer is in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator voltage: 45kV, generator electricity Stream：40mA, step-length: 0.02 ° of 2 θ, X'celeratorTMRTMS (Real Time Multi-Strip) detector.Incident beam The setting of side: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °) and 10mm light beams are covered Mould.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slits.
Table II
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The drawing of compound A free alkalis hydrate 1 Graceful spectrum shows in figure 6, it was observed that main peaks be located at 582.9,744.4,776.1,859.7,896.0,999.8, 1239.7、1278.0、1345.9、1372.5、1392.1、1428.9、1468.0、1488.3、1529.6、1572.1、1621.2、 1732.7、3000.4cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and show in the figure 7.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A dissociates The DSC thermal analysis curues display heat absorption for the first time of buck compound 1 with about 64 DEG C of initial temperature, about 96 DEG C of peak temperature and 249.8J/g enthalpy, then second heat absorption is with about 123 DEG C of initial temperature, about 146 DEG C of peak temperature and 93.4J/g's Enthalpy.Skilled artisan recognize that initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and show in fig. 8.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A free alkalis hydrate 1 observe two before being shown in final thermal decomposition The weight loss event in individual stage.Temperature range at 30 DEG C to 100 DEG C occurs for first time weight loss event, and weight loss is about 9.7%.Temperature range at 100 DEG C to 150 DEG C, weight loss about 3.1% occur for second of weight loss event.
Embodiment 194：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - Second crystalline hydrate (the compound A of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Free alkali hydrate 2)
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) suspension of urea in ethanol 3 days, while in 40 DEG C and 5 DEG C Between temperature cycles.By isolated by vacuum filtration solid, air-dry 1 hour, then obtained in vacuum drying oven in 40 DEG C of dryings In the title compound of crystalline solid.
X-ray powder diffraction (XRPD) pattern displaying of compound A free alkalis hydrate 2 in fig .9, between the angle of diffraction and d- Away from general introduction be given in Table III below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer Diffractometer is in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator voltage: 45kV, generator electricity Stream：40mA, step-length: 0.02 ° of 2 θ, X'celeratorTMRTMS (Real Time Multi-Strip) detector.Incident beam The setting of side: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °) and 10mm light beams are covered Mould.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slits.
Table III
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The drawing of compound A free alkalis hydrate 2 Graceful spectrum shows in Fig. 10, it was observed that main peaks be located at 541.0,579.9,609.4,664.3,696.7,719.2, 773.7、792.4、817.3、901.9、945.5、987.5、1211.1、1246.6、1312.2、1331.9、1362.2、 1398.1、1428.5、1465.5、1487.2、1535.5、1579.1、1617.4、2943.7、2998.9、3096.1cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and show in fig. 11.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A dissociates The DSC thermal analysis curues display heat absorption for the first time of buck compound 2 with about 46 DEG C of initial temperature, about 67 DEG C of peak temperature and 18.78J/g enthalpy, then second heat absorption is with about 155 DEG C of initial temperature, about 164 DEG C of peak temperature and 1.15J/g's Enthalpy, third time heat absorption afterwards is with about 195 DEG C of initial temperature, about 205 DEG C of peak temperature and 53.81J/g enthalpy, and then the 4th Secondary heat absorption is with about 240 DEG C of initial temperature, about 245 DEG C of peak temperature and 49.10J/g enthalpy.Those skilled in the art should Recognizing initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and show in fig. 12.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A free alkalis hydrate 2 are observed many before being shown in final thermal decomposition Secondary weight loss event.Temperature range at 25 DEG C to 100 DEG C occurs for first time weight loss event, and weight loss is about 3.7%.Temperature range at 130 DEG C to 175 DEG C, weight loss about 1.9% occur for second of weight loss event.For the last time Temperature range at 175 DEG C to 210 DEG C, weight loss about 3.3% occur for weight loss event.Do not seen at less than 225 DEG C Observe thermal decomposition.
Embodiment 195：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - 3rd crystalline hydrate (the compound A of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Free alkali hydrate 3)
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea is 9:1 acetone：Suspension in water 3 days, while 40 DEG C and 5 DEG C between temperature cycles.By isolated by vacuum filtration solid, air-dry 1 hour, it is then dry in 40 DEG C in vacuum drying oven It is dry, obtain the title compound in crystalline solid.X-ray powder diffraction (XRPD) pattern of compound A free alkalis hydrate 3 shows Show in fig. 13, the general introduction of the angle of diffraction and d- spacing is given in Table IV below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer diffractometers in zero-background wafers of Si in carrying out.Acquisition condition includes：Cu KαRay, Generator voltage: 45kV, generator electric current：40mA, step-length: 0.02 ° of 2 θ, X'celeratorTM RTMS(Real Time Multi-Strip) detector.The setting of incident beam side: fixed divergent slit (0.25 °), 0.04rad Soller slits are anti- Scatter slit (0.25 °) and 10mm light beam masks.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slit.
Table IV
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The drawing of compound A free alkalis hydrate 3 Graceful spectrum shows in fig. 14, it was observed that main peaks be located at 542.9,587.4,671.6,696.4,719.1,775.4, 794.7、817.6、900.8、949.6、988.4、1246.5、1316.2、1333.2、1361.8、1399.2、1430.4、 1463.4、1486.2、1534.7、1580.2、1616.9、2942.3、3001.5、3094.6cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and show in fig .15.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A dissociates The DSC thermal analysis curues display heat absorption for the first time of buck compound 3 with about 56 DEG C of initial temperature, about 75 DEG C of peak temperature and 18.16J/g enthalpy, then second heat absorption is with about 89 DEG C of initial temperature, about 106 DEG C of peak temperature and 17.62J/g's Enthalpy, third time heat absorption afterwards is with about 187 DEG C of initial temperature, about 196 DEG C of peak temperature and 42.13J/g enthalpy, and then the 4th Secondary heat absorption is with about 237 DEG C of initial temperature, about 242 DEG C of peak temperature and 30.77J/g enthalpy.Those skilled in the art should Recognizing initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and show in figure 16.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A free alkalis hydrate 3 are observed many before being shown in final thermal decomposition Secondary weight loss event.Temperature range at 25 DEG C to 63 DEG C occurs for first time weight loss event, and weight loss is about 4.3%.Temperature range at 63 DEG C to 100 DEG C, weight loss about 2.5% occur for second of weight loss event.For the last time Temperature range at 100 DEG C to 210 DEG C, weight loss about 3.9% occur for weight loss event.Do not seen at less than 225 DEG C Observe thermal decomposition.
Embodiment 196：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - 4th crystalline hydrate (the compound A of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Free alkali hydrate 4)
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3-base) suspension of the urea in 2-methyl cellosolve 3 days, while Temperature cycles between 40 DEG C and 5 DEG C.By isolated by vacuum filtration solid, air-dry 1 hour, then in 40 DEG C in vacuum drying oven Dry, obtain the title compound in crystalline solid.
X-ray powder diffraction (XRPD) pattern displaying of compound A free alkalis hydrate 4 in fig. 17, the angle of diffraction and d- The general introduction of spacing is given in Table V below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer Diffractometer is in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator voltage: 45kV, generator electricity Stream：40mA, step-length: 0.02 ° of 2 θ, X'celeratorTMRTMS (Real Time Multi-Strip) detector.Incident beam The setting of side: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °) and 10mm light beams are covered Mould.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slits.
Table V
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The drawing of compound A free alkalis hydrate 4 Graceful spectrum shows in figure 18, it was observed that main peaks be located at 550.9,680.5,747.5,776.0,856.6,894.3, 954.6、1002.6、1088.1、1240.5、1277.7、1314.5、1343.9、1390.6、1439.9、1463.3、1491.7、 1532.6、1569.5、1613.3、1650.6、1729.1、2940.4、2998.1cm-1。
In 40mL/minN2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and be shown in Figure 19.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A dissociates The DSC thermal analysis curues display heat absorption for the first time of buck compound 4 with about 63 DEG C of initial temperature, about 92 DEG C of peak temperature and 81.38J/g enthalpy, then second heat absorption is with about 194 DEG C of initial temperature, about 198 DEG C of peak temperature and 44.70J/g's Enthalpy, third time heat absorption afterwards is with about 242 DEG C of initial temperature, about 244 DEG C of peak temperature and 2.939J/g enthalpy.This area skill Art personnel will be appreciated that initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and show in fig. 20.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A free alkalis hydrate 4 are observed many before being shown in final thermal decomposition Secondary weight loss event.Temperature range at 25 DEG C to 110 DEG C occurs for first time weight loss event, and weight loss is about 3.9%.Temperature range at 155 DEG C to 210 DEG C, weight loss about 1.2% occur for second of weight loss event.Less than Thermal decomposition is not observed at 225 DEG C.
Embodiment 197：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - 5th crystalline hydrate (the compound A of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea free alkali Free alkali hydrate 5)
Stir 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea is 19:1 acetone：Suspension in water 3 days, while 40 DEG C and 5 DEG C between temperature cycles.By isolated by vacuum filtration solid, air-dry 1 hour, it is then dry in 40 DEG C in vacuum drying oven It is dry, obtain the title compound in crystalline solid.
X-ray powder diffraction (XRPD) pattern displaying of compound A free alkalis hydrate 5 in figure 21, the angle of diffraction and d- The general introduction of spacing is given in Table VI below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer diffractometers are in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator electricity Pressure: 45kV, generator electric current：40mA, step-length: 0.02 ° of 2 θ, X'celeratorTM RTMS(Real Time Multi-Strip) Detector.The setting of incident beam side: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °) and 10mm light beam masks.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Suo Le seams Gap.
Table VI
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The drawing of compound A free alkalis hydrate 5 Graceful spectrum shows in fig. 22, it was observed that main peaks be located at 542.9,581.1,664.4,696.3,719.5,774.8, 793.9、817.9、898.4、944.0、988.9、1109.8、1247.0、1315.3、1332.8、1399.4、1429.9、 1464.5、1486.7、1533.4、1580.3、1617.5、2938.9、2998.5、3098.4cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and show in fig 23.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A dissociates The DSC thermal analysis curues display heat absorption for the first time of buck compound 5 with about 36 DEG C of initial temperature, about 64 DEG C of peak temperature and 97.61J/g enthalpy, then second heat absorption is with about 148 DEG C of initial temperature, about 155 DEG C of peak temperature and 0.2688J/g's Enthalpy, third time heat absorption afterwards is with about 181 DEG C of initial temperature, about 198 DEG C of peak temperature and 51.45J/g enthalpy.This area skill Art personnel will be appreciated that initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and show in fig. 24.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A free alkalis hydrate 5 are observed many before being shown in final thermal decomposition Secondary weight loss event.Temperature range at 25 DEG C to 105 DEG C occurs for first time weight loss event, and weight loss is about 7.7%.Temperature range at 105 DEG C to 175 DEG C, weight loss about 3.4% occur for second of weight loss event.For the last time Temperature range at 175 DEG C to 225 DEG C occurs for weight loss event, and weight loss is about 3.9%.Do not have at less than 225 DEG C It was observed that thermal decomposition.
Embodiment 198:1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - Crystal anhydrous hydrochloride (the compound A hydrochlorides of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea Anhydride)
·HCl
By 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) suspension of urea in acetone is heated to 40 DEG C.Add monovalent 3M aqueous hydrochloric acid solutions, and the slurries are stirred 2 days, while the temperature range within one hour period between 40 DEG C and 5 DEG C is followed Ring, is then balanced 4 hours at room temperature.Filter solid is crossed, is air-dried, and is washed with acetone, the title compound in crystalline solid is obtained Thing.Ion chromatography analysis indicate 1：1 acid：Free alkali stoichiometry.
X-ray powder diffraction (XRPD) pattern displaying of compound A hydrochloride anhydrides in fig. 25, between the angle of diffraction and d- Away from general introduction be given in Table VII below.XRPD analyses are in PANanalytVIIcal X ' Pert Pro DVIIffractometer diffractometers are in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator electricity Pressure: 45kV, generator electric current：40mA, step-length: 0.02 ° of 2 θ, X'celeratorTM RTMS(Real Time Multi-Strip) Detector.The setting of incident beam side: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °), and 10mm light beam masks.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Suo Le seams Gap.
Table VII
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The Raman of compound A hydrochloride anhydrides Spectrum shows in fig. 26, it was observed that main peaks be located at 589.0,734.4,768.5,893.3,1177.3,1203.0, 1257.1、1374.9、1475.7、1602.0、1715.5、2993.2cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and show in figure 27.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A hydrochloric acid The sharp endothermic peak of DSC thermal analysis curues display of salt anhydride, with about 221 DEG C of initial temperature, about 232 DEG C of peak temperature and 185.8J/g enthalpy.Skilled artisan recognize that initial temperature, peak temperature and the enthalpy of heat absorption may be according to experiment bars Part and change.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and be shown in Figure 28.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A hydrochloride anhydrides are shown in 25 DEG C to 150 DEG C of temperature range Minimum weight loses event, and weight loss is about 0.2%.Thermal decomposition is not observed at less than 200 DEG C.
Embodiment 199：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - Crystalline hydrate (the compound A hydrochloric acid of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea hydrochloride Salt hydrate)
·H2O
·HCl
By 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) suspension of the urea in acetonitrile is heated to 40 DEG C.Add monovalent 3M aqueous hydrochloric acid solutions, and stir the slurries and stay overnight, while the temperature range within one hour period between 40 DEG C and 5 DEG C is followed Ring, is then balanced 1 hour at room temperature.Filter solid is crossed, is air-dried, and is washed with acetonitrile, the title compound in crystalline solid is obtained Thing.
X-ray powder diffraction (XRPD) pattern displaying of compound A hydrochloride hydrates is in Figure 29, between the angle of diffraction and d- Away from general introduction be given in Table VIII below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer diffractometers are in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator electricity Pressure: 45kV, dynamo current: 40mA, step-length: 0.02 ° of 2 θ, X'celeratorTM RTMS(Real Time Multi-Strip) Detector.The setting of incident beam side: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °), and 10mm light beam masks.The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Suo Le seams Gap.
Table VIII
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The Raman of compound A hydrochloride hydrates Spectrum shows in fig. 30, it was observed that main peaks be located at 213.1,456.7,575.1,704.6,735.5,770.1,885.3, 934.8、1232.5、1256.0、1369.8、1493.3、1548.5、1578.9、1612.9、1722.2、2918.2cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and be shown in Figure 31.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A hydrochloric acid The DSC thermal analysis curues display heat absorption for the first time of salt hydrate with about 115 DEG C of initial temperature, about 157 DEG C of peak temperature and 100.5J/g enthalpy, then second heat absorption is with about 187 DEG C of initial temperature, about 198 DEG C of peak temperature and 114.9J/g's Enthalpy.Skilled artisan recognize that initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and be shown in Figure 32.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A hydrochloride hydrates are shown in 25 DEG C to 180 DEG C of temperature range Weight loss event, weight loss is about 3.6%.Thermal decomposition is not observed at less than 200 DEG C.
Embodiment 200：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - Crystallization esilate (the compound A ethyl sulfonic acids of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea Salt)
By 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) suspension of the urea in acetonitrile is heated to 40 DEG C.Add monovalent The 3M ethyl sulfonic acid aqueous solution, and stir the slurries and stay overnight, while the temperature range within one hour period between 40 DEG C and 5 DEG C Circulation, is then balanced 1 hour at room temperature.Filter solid is crossed, is air-dried, and is washed with acetonitrile, is obtained in the titled of crystalline solid Compound.1H NMR analyses indicate 1：1 acid：Alkali stoichiometry.
X-ray powder diffraction (XRPD) pattern displaying of compound A esilates in fig. 33, the angle of diffraction and d- spacing General introduction is given in Table IX below.XRPD analyses are in PANanalytIIcal X ' Pert Pro DIIffractometer diffraction Count in carrying out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator voltage: 45kV, generator electric current： 40mA, step-length: 0.02 ° of 2 θ, X'celeratorTMRTMS (Real Time Multi-Strip) detector.Incident beam side Set: fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °) and 10mm light beam masks. The setting of diffracted beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slits.
Table ix
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The Raman light of compound A esilates Spectrum be shown in Figure 34, it was observed that main peaks be located at 195.0,432.2,734.5,749.7,882.2,1046.1,1211.4, 1240.4、1380.1、1422.3、1502.1、1600.0、1617.0、1713.9、2937.7cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and be shown in Figure 35.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A second sulphurs The sharp endothermic peak of DSC thermal analysis curues display of hydrochlorate, with about 236 DEG C of initial temperature, about 239 DEG C of peak temperature and 140.7J/g Enthalpy.Skilled artisan recognize that initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and be shown in Figure 36.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The TGA thermal analysis curues of compound A esilates are shown in the minimum of 25 DEG C to 180 DEG C of temperature range Weight loss event, weight loss is about 0.14%.Thermal decomposition is not observed at less than 200 DEG C.
Embodiment 201：1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) - The crystalline sulfuric acid salt (compound A sulfate) of 3- (5- (the fluoro- 2- methylpropanes -2- bases of 1,1,1- tri-) isoxazole -3-base) urea
By 1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1, The fluoro- 2- methylpropanes -2- bases of 1,1- tri-) isoxazole -3-base) suspension of the urea in acetonitrile is heated to 40 DEG C.Add monovalent 2.5M aqueous sulfuric acids, and stir the slurries and stay overnight, while the temperature range within one hour period between 40 DEG C and 5 DEG C Circulation, is then balanced 1 hour at room temperature.Filter solid is crossed, is air-dried, and is washed with acetonitrile, is obtained in the titled of crystalline solid Compound.Ion chromatography indicates 1：1 acid：Alkali stoichiometry.
X-ray powder diffraction (XRPD) pattern displaying of compound A sulfate in Figure 37, the angle of diffraction and d- spacing it is general State and be given in Table X below.XRPD analysis be PANanalytIIcal X ' Pert Pro DIIffractometer diffractometers in Carried out in zero-background wafers of Si.Acquisition condition includes：Cu KαRay, generator voltage: 45kV, generator electric current：40mA, Step-length: 0.02 ° of 2 θ, X'celeratorTMRTMS (Real Time Multi-Strip) detector.The setting of incident beam side: Fixed divergent slit (0.25 °), 0.04rad Soller slits, anti-scatter slit (0.25 °), and 10mm light beam masks.Diffraction The setting of light beam side: fixed divergent slit (0.25 °) and 0.04rad Soller slits.
Table X
The Raman spectrum of record header compound on the FT-Raman Spectrometer of Nicolet NXR 9650, 4cm-1Resolution ratio, using from Nd:The excitation wavelength (λ=1064nm) of YVO4 laser.The Raman spectrum of compound A sulfate shows Show in Figure 38, it was observed that main peaks be located at 202.1,572.0,697.9,737.5,777.3,937.1,1181.1, 1264.9、1370.0、1499.4、1554.8、1602.3、1723.7、2942.8cm-1。
In 40mL/min N2Under purging, in the TA Instruments equipped with automatic sampler and refrigerating/cooling system Differential scanning calorimetry (DSC) heat of record header compound on Q100 Differential Scanning Calorimeter Analysis chart, and be shown in Figure 39.In crimping aluminium dish, tested using the 15 DEG C/min rate of heat addition.Compound A sulfuric acid The DSC thermal analysis curues display heat absorption for the first time of salt with about 30 DEG C of initial temperature, about 77 DEG C of peak temperature and 28.76J/g's Enthalpy, then second of heat absorption is with about 214 DEG C of initial temperature, about 218 DEG C of peak temperature and 164.0J/g enthalpy.This area skill Art personnel will be appreciated that initial temperature, peak temperature and the enthalpy of heat absorption may change according to experiment condition.
The heat of record header compound on TA Instruments Q500 Thermogravimetric Analyzer Gravimetric analysis (TGA) thermal analysis curue, and be shown in Figure 40.In aluminium dish, with 40mL/min N2It is air-flow and 15 DEG C/min plus Hot speed is tested.The weight that the TGA thermal analysis curues of compound A sulfate are shown in 30 DEG C to 160 DEG C of temperature range is damaged Have an accident part, and weight loss is about 1.3%.Thermal decomposition is not observed at less than 200 DEG C.
Bioanalysis
The enzyme analysis of RET kinases
Using baculovirus expression system, by mankind's RET kinases cytoplasmic domain (registration number NP_000314.1 ammonia Base acid 658-1114) it is expressed as N- ends GST- fusion proteins.Use glutathione agarose chromatogram purification GST-RET.With total The RET kinase inhibitors of volume 10uL progressive concentrations in 384 casement plates, are carried out as follows RET kinases enzyme process point as monomer Analysis：RET inhibitor compounds are prepared by the following procedure：The RET inhibitor of 100nL various concentrations is added in 384- orifice plates.By 5 2X enzymatic mixtures (the 50mM HEPES (4- (2- ethoxys) -1- piperazine ethanesulfonic acids) in μ L/ holes；1mM CHAPS (3- [(3- courage acyls Amine propyl group (cholamidopropyl)) dimethylammonio (ammonio)] -1- propane sulfonic acid salt)；0.1mg/mL BSA (cow's serums Albumin)；1mM DTT (dithiothreitol (DTT))；0.2nM RET kinases) it is added in 384 orifice plate, and cultivate 30 at 23 DEG C Minute.Add 2X substrate mixtures (the 50mM HEPES in 5 μ L/ holes；1mM CHAPS；0.1mg/mL BSA；20 μM of adenosine tripho hates； 20mM MgCl2With the biotinylated peptide substrates of 1mM), and cultivated 1 hour at 23 DEG C.At 23 DEG C, 10 μ L/ hole 2X of culture stop Only/detection mixture (50mM HEPES；0.1%BSA；800mM potassium fluorides；50mM EDTA (ethylenediamine tetra-acetic acid)；Europium is cave-shaped The 200X dilutions of the anti-phosphotyrosine antibody of compound label；62.5nM streptavidins-XL665) 1 hour, and Reading on Homogenous Time-Resolved Fluorescence reading machines.Using GraphPad Prism by IC50Fitting To S-shaped dose response curve.
Biological analysis
Have detected embodiments of the invention compound in above-mentioned RET analyses, find the embodiment compound be with IC5010 μM of ＜ RET inhibitor.The data of the specific embodiment detected in the enzyme analysis of mankind's RET kinases are listed in such as table 1 below In：+=10 μM>IC50>500nM；++=500nM >=IC50>100nM；+++=IC50≤100nM。
Table 1
Analysis on Mechanism of the RET kinases based on cell
It in the analysis based on cell, can detect that the compound of the present invention suppresses the work(of composing type RET tyrosine phosphorylations Effect.By TT cells (ATCC CRL-1803), a kind of medullary thyroid carcinoma cell line that RET kinases is activated with composing type is kept 150cm at 37 DEG C2The F12Kaighn's culture mediums in 5% carbon dioxide, 10% hyclone, 1X in ware In Glutamax, 1X nonessential amino acid, 1X Pen/Strep antibiotic.1.0E5TT cells/wells are added to 96 hole cell trainings Support in plate, and stay overnight its adhesion.At 37 DEG C, handled in 5% carbon dioxide with the RET inhibitor compounds of various concentrations TT cells, are washed with ice-cold PBS (phosphate buffered saline (PBS)), and by adding 200 μ L 25mM Tris HCl pH 7.5； 2mM EDTA；150mM NaCl；1% NaTDC；1%Triton X-100；50mM β phosphoglycerol sodium；1mM ortho-vanadic acids Sodium；1X phosphatase inhibitor cocktails #2 (Sigma#P5726)；1X phosphatase inhibitor cocktails #3 (Sigma#P0044) and 1X is completely small-sized to be cultivated 10 minutes without EDTA protease inhibitor cocktails (Roche#4693159001) cracking at -80 DEG C, And thawed on ice.At 4 DEG C, 100 μ L TT product of cell lysis is added in 96 orifice plates overnight, the plate is 4 1X PBS are used at DEG C；0.05% Tween-20；The anti-RET antibody (Cell of rabbit that 1% bovine serum albumin(BSA) is blocked Signaling#_7032) 1：The coating of 1,000 dilutions is stayed overnight.The plate is washed into 4X with 200 μ L 1X PBS；Add 0.05% Tween-20, then adds the 1 of 100 μ L anti-phosphotyrosine detection antibody (Cell Signaling#_7034)： 1,000 dilution, and cultivated 1 hour at 37 DEG C.The plate is washed into 4X with 200 μ L 1X PBS；Add 0.05% tween- 20, then add 100 μ L anti-mouse immunoglobulin horseradish peroxidase binding antibody (Cell Signalin#_ 7034), and at 37 DEG C cultivate 1 hour.The plate is washed into 4X with 200 μ L 1X PBS；Add 0.05% Tween-20,100 μ L TMB (3,3', 5,5 "-tetramethyl benzidine) substrate (Cell Signaling#_7004), cultivated 10 minutes at 37 DEG C, plus Enter 100 μ L terminate liquid (Cell Signaling#_7002), and absorbance is read in 450nm on spectrophotometer.Use GraphPad Prism are by IC50It is fitted to S-shaped dose response curve.
Proliferation assay of the RET kinases based on cell
It can detect that the compound of the present invention suppresses effect of cell propagation and the ability of cell survival.By TT cells (ATCC CRL-1803), a kind of medullary thyroid carcinoma cell line that RET kinases is activated with composing type, is maintained at 37 DEG C 150cm2F12 Kaighn's culture mediums, 10% hyclone, 1X Glutamax, 1X in ware in 5% carbon dioxide is nonessential In amino acid, 1X Pen/Strep antibiotic.6.0E3TT cells/wells in 50 μ L culture mediums are added to 96 hole cell trainings Support in plate, and stay overnight their adhesion.The RET inhibitor compounds of 50 μ l serial dilution are added to the TT containing culture In 96 orifice plates of cell, and at 37 DEG C, cultivated eight days in 5% carbon dioxide.Add 50 μ L CellTiter-Glo (Promega#_G-7573) inclusion, and on agitator is mixed 1 minute, then lucifuge 10 minutes at 23 DEG C, and passing through EnVision (PErkinElmer) reads luminous.Using GraphPad Prism by IC50It is fitted to S-shaped dose response curve.
The super quick model of internal colon
Effect (Hoffman, J.M., the et of RET kinase inhibitor compounds are evaluated in the super quick In vivo model of colon al.,Gastroenterology,2012,142：844-854).

Claims (24)

1. according to the compound or its pharmaceutically-acceptable salts of formula (I):
Wherein:
X is N or CR5；
Y is key or-O-；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6；
R1For hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl or (C3-C6) cycloalkyl；
R2And R3It is each independently selected from hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-and ((C1- C6) alkyl) ((C1-C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3- C6) cycloalkyloxy is optionally by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
R4For phenyl or 5- or 6- unit's heteroaryls, it is each optionally by one, two or three independently selected from following substitutions Base replaces：Halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, phenyl, 5- or 6- unit's heteroaryls, Hydroxyl ,-OR7、-CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) Alkoxy, halo (C1-C4) alkoxy ,-NR8R9Or-CONR8R9Substitution；And wherein described 5- or 6- unit's heteroaryls substituent Optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
R5For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alkoxy, halogen Generation (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkyl) ((C1-C6) alkane Base) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3-C6) cycloalkyloxy is optionally By hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
Or R3And R5Carbon atom in connection be combined together expression 5- or 6- yuan of rings, optionally comprising one, two or Three hetero atoms independently selected from nitrogen, oxygen and sulphur, wherein the ring optionally by one or two independently selected from following Substituent replaces：Halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alkoxy, halogen Generation (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino-and ((C1-C4) alkyl) ((C1-C4) alkane Base) amino；
Each R6Independently selected from halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-and ((C1- C6) alkyl) ((C1-C6) alkyl) amino-；
R7For (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or 4- be to 6- circle heterocycles alkyl；Wherein described (C1- C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；And wherein institute State (C3-C6) cycloalkyl optionally replaces by one or two independently selected from following substituents：(C1-C4) alkyl, halo (C1-C4) alkyl, hydroxyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy and halo (C1-C4) alkoxy；And wherein described 4- is extremely 6- circle heterocycles alkyl is optionally by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) substituent of alkyl takes Generation；With
R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, amino (C1-C4) alkyl-, ((C1-C4) Alkyl) amino (C1-C4) alkyl-and ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C1-C4) alkyl-；
Or R8And R9Nitrogen in connection is combined together the ring for representing 5- or 6- member saturations, optionally containing selected from oxygen, nitrogen With the other hetero atom of sulphur, wherein the ring is optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl or hydroxyl (C1- C4) alkyl substitution；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- phenyl Urea, 1- (5- (tert-butyl group) isoxazole -3-bases) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- second Base phenyl) -3- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) urea, 1- (4- ((6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) epoxide) phenyl) -3- (p- tolyl) urea, 1- (4- ((6- oxo -1,6- dihydropyridine -3- bases) epoxide) benzene Base) -3- (3- (trifluoromethyl) phenyl) ureas or 1- (4- (tert-butyl group) phenyl) -3- (4- ((6- oxo -1,6- dihydropyridines -3- Base) epoxide) phenyl) urea.
2. compound according to claim 1 or pharmaceutically-acceptable salts, are represented by formula (XII)：
Wherein：
A is N or CR13；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6；
R2And R3It is each independently selected from hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-and ((C1- C6) alkyl) ((C1-C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3- C6) cycloalkyloxy is optionally by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
R5For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alkoxy, halogen Generation (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkyl) ((C1-C6) alkane Base) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3-C6) cycloalkyloxy is optionally By hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
Or R3And R5Carbon atom in connection be combined together expression 5- or 6- yuan of rings, optionally comprising one, two or Three hetero atoms independently selected from nitrogen, oxygen and sulphur, wherein the ring optionally by one or two independently selected from following Substituent replaces：Halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alkoxy, halogen Generation (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino-and ((C1-C4) alkyl) ((C1-C4) alkane Base) amino；
Each R6Independently selected from halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-and ((C1- C6) alkyl) ((C1-C6) alkyl) amino-；
R7For (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or 4- be to 6- circle heterocycles alkyl；Wherein described (C1- C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；And it is wherein described (C3-C6) cycloalkyl optionally replaces by one or two independently selected from following substituents：(C1-C4) alkyl, halo (C1- C4) alkyl, hydroxyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy and halo (C1-C4) alkoxy；And wherein described 4- to 6- Circle heterocycles alkyl is optionally by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) substituent of alkyl takes Generation；
R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, amino (C1-C4) alkyl-, ((C1-C4) Alkyl) amino (C1-C4) alkyl-and ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C1-C4) alkyl-；
Or R8And R9Nitrogen in connection is combined together the ring for representing 5- or 6- member saturations, optionally containing selected from oxygen, nitrogen With the other hetero atom of sulphur, wherein the ring is optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl or hydroxyl (C1- C4) alkyl substitution；
R10For hydrogen, halogen or (C1-C4) alkoxy；
R11For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, 5- or 6- unit's heteroaryls, Hydroxyl ,-OR7Or-CONR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1- C4) alkoxy or-NR8R9Substitution；And wherein described 5- or 6- unit's heteroaryls are optionally by halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
R12For hydrogen, halogen or halo (C1-C4) alkyl；With
R13For hydrogen, halogen, halo (C1-C4) alkyl or 5- or 6- unit's heteroaryls, wherein 5- the or 6- unit's heteroaryls are optionally By halogen, (C1-C4) alkyl or halo (C1-C4) alkyl substitution；
Condition is that the compound is not 1- (4- (5- hydroxyl -1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- phenyl Urea；
Condition is when A is CR13When, R10、R11、R12And R13At least one be hydrogen.
3. compound according to claim 1 or pharmaceutically-acceptable salts, are represented by formula (XIX)：
Wherein：
A1、A2And A3In one be selected from O, S and NR15, and other two is each independently selected from N and CH；
Z1、Z2、Z3And Z4It is each independently N, CH or CR6；
R2And R3It is each independently selected from hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-and ((C1- C6) alkyl) ((C1-C6) alkyl) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3- C6) cycloalkyloxy is optionally by hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
R5For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C6) alkoxy, halogen Generation (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-or ((C1-C6) alkyl) ((C1-C6) alkane Base) amino-；Wherein described (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy or (C3-C6) cycloalkyloxy is optionally By hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy or (C3-C6) cycloalkyloxy substitution；
Or R3And R5Carbon atom in connection be combined together expression 5- or 6- yuan of rings, optionally comprising one, two or Three hetero atoms independently selected from nitrogen, oxygen and sulphur, wherein the ring optionally by one or two independently selected from following Substituent replaces：Halogen, (C1-C4) alkyl, halo (C1-C4) alkyl, (C3-C6) cycloalkyl, hydroxyl, (C1-C4) alkoxy, halogen Generation (C1-C4) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C4) alkyl) amino-and ((C1-C4) alkyl) ((C1-C4) alkane Base) amino；
Each R6Independently selected from halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl, (C1-C6) alkoxy, halo (C1-C6) alkoxy, (C3-C6) cycloalkyloxy, amino, ((C1-C6) alkyl) amino-and ((C1- C6) alkyl) ((C1-C6) alkyl) amino-；
R7For (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or 4- be to 6- circle heterocycles alkyl；Wherein described (C1- C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；And it is wherein described (C3-C6) cycloalkyl optionally replaces by one or two independently selected from following substituents：(C1-C4) alkyl, halo (C1- C4) alkyl, hydroxyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy and halo (C1-C4) alkoxy；And wherein described 4- to 6- Circle heterocycles alkyl is optionally by one or two independently selected from (C1-C4) alkyl and halo (C1-C4) substituent of alkyl takes Generation；
R8And R9It is each independently selected from hydrogen, (C1-C4) alkyl, halo (C1-C4) alkyl, amino (C1-C4) alkyl-, ((C1-C4) Alkyl) amino (C1-C4) alkyl-and ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C1-C4) alkyl-；
Or R8And R9Nitrogen in connection is combined together the ring for representing 5- or 6- member saturations, optionally containing selected from oxygen, nitrogen With the other hetero atom of sulphur, wherein the ring is optionally by halogen, (C1-C4) alkyl, halo (C1-C4) alkyl or hydroxyl (C1- C4) alkyl substitution；
R14For hydrogen, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl, cyano group, hydroxyl ,-OR7、- CONR8R9、-SO2R7With-SO2NR8R9；Wherein described (C1-C6) alkyl is optionally by cyano group, hydroxyl, (C1-C4) alkoxy, halo (C1-C4) alkoxy or-NR8R9Substitution；With
R15For hydrogen, (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C6) cycloalkyl or phenyl.
4. compound according to claim 1 or pharmaceutically-acceptable salts, wherein X are CR5。
5. according to claim 1 or the compound or pharmaceutically-acceptable salts of claim 4, wherein Y is key.
6. according to the compound or pharmaceutically-acceptable salts of claim 1,4 or 5, wherein R1For hydrogen.
7. according to the compound or pharmaceutically-acceptable salts of claim 1,4,5 or 6, wherein R4For phenyl, it is optionally by one It is individual, two or three replace independently selected from following substituent：Fluorine, chlorine, (C1-C6) alkyl, halo (C1-C4) alkyl, cyanogen Base, (C1-C4) alkoxy, hydroxyl (C2-C4) alkoxy-, (C1-C4) alkoxy (C2-C4) alkoxy-, amino (C2-C4) alcoxyl Base-, ((C1-C4) alkyl) amino (C2-C4) alkoxy-, ((C1-C4) alkyl) ((C1-C4) alkyl) amino (C2-C4) alcoxyl Base -, (3- methy oxetane -3- bases) epoxide-and-CONH2；Wherein described (C1-C6) alkyl optionally by cyano group, hydroxyl, (C1-C4) alkoxy, amino, ((C1-C4) alkyl) amino-or ((C1-C4) alkyl) ((C1-C4) alkyl) amino substitution.
8. according to the compound or pharmaceutically-acceptable salts of claim 1,4,5 or 6, wherein R4For furyl, thienyl, pyrroles Base, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, oxazolyls, thiazolyl, isoxazolyls, isothiazolyl, oxadiazolyls, thiophene two Oxazolyl, pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals or triazine radical, its each optionally by one or two independently selected from (C1-C4) alkyl and halogen (C1-C4) alkyl substituent substitution.
9. compound as claimed in one of claims 1-8 or pharmaceutically-acceptable salts, wherein Z1、Z2、Z3And Z4In 0,1 or 2 Individual is N and Z1、Z2、Z3And Z4In 0,1 or 2 be CR6。
10. compound as claimed in one of claims 1-9 or pharmaceutically-acceptable salts, wherein R2For hydrogen, (C1-C4) alkyl Or (C1-C4) alkoxy.
11. compound as claimed in one of claims 1-10 or pharmaceutically-acceptable salts, wherein R3For hydrogen, hydroxyl, (C1- C4) alkoxy or (C3-C6) cycloalkyloxy.
12. according to any one of claim 1-11 compound or pharmaceutically-acceptable salts, wherein R5For hydrogen, hydroxyl, (C1- C4) alkoxy or (C3-C6) cycloalkyloxy.
13. according to any one of claim 1-12 compound or pharmaceutically-acceptable salts, wherein each R6Independently selected from Fluorine, chlorine, methyl, ethyl, difluoromethyl, cyclopropyl, methoxyl group, isopropoxy and dimethylamino-.
14. compound according to claim 1, it is:
1- (the fluoro- 4- of 2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (3- (4- methyl isophthalic acid H- imidazoles - 1- yls) -5- (trifluoromethyl) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (1- oxo -2,5,6,7- tetrahydrochysene -1H- cyclopentadiene And [c] pyridin-4-yl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydro-1 h-pyrazoles simultaneously [4,3-c] pyridin-7-yl) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- isopropoxies - 3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro - [2,3'- bipyridyls] -5- bases) urea；
1- (the fluoro- 4- of 2- (5- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -2- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- isopropoxies - 3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- (3- hydroxyls - 2,2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- hydroxyl second Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (5- (fluoro- 2- first of 1,1,1- tri- Base propane -2- base) isoxazole -3-bases) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methyl oxygen Azetidine -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methyl oxygen Azetidine -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- Fluoro- 2- methylpropanes -2- base) isoxazole -3-bases) urea；
1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (5- (1,1,1- tri- Fluoro- 2- methylpropanes -2- base) isoxazole -3-bases) urea；
1- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- (piperazine -1- ylmethyls) -3- (trifluoromethyl) benzene Base) urea；
1- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ring propoxyl group -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- rings Butane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- methoxyl group -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes -3- Base) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- oxo -2,3,4,5- tetrahydrofurans simultaneously [3,2-c] pyridin-7-yl) phenyl) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea；
1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea；
1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxyls third Alkane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (6- (2- hydroxyls third Alkane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (2- (difluoromethyl) -4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((4- ethyls Piperazine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((4- ethyl piperazidines -1- Base) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazines Piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) -3- (4- ((4- second Base piperazine -1- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (4- ethyoxyl -2- oxo -1,2- dihydro-pyrimidin -5- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 5-) phenyl) -3- (4- ((3- methy oxetanes -3- Base) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (the fluoro- 6- oxos -1,6- dihydropyridines -3- bases of 4-) phenyl) -3- (4- ((3- methy oxetanes -3- Base) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) Phenyl) urea；
1- (6- (2- hydroxy propane -2- bases) -5- (trifluoromethyl) pyridin-3-yl) -3- (4- methyl -2- (7- oxos -6,7- two Hydrogen furans simultaneously [2,3-c] pyridin-4-yl) pyrimidine -5- bases) urea；
1- (the fluoro- 4- of 2- (2- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- (3- hydroxyl -2, 2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (trifluoromethyl) Phenyl) urea；
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- first Yl pyrimidines -5- bases) urea；
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- first Yl pyrimidines -5- bases) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (morpholinomethyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (5- (1,1,1- tri- Fluoro- 2- methylpropanes -2- base) isoxazole -3-bases) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2, 2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (3- hydroxyl -2, 2- dimethyl propyls) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxyls third Alkane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl - 1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4,6- dimethyl pyrimidine -5- bases) -3- (3- (4- first Base -1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl Pyrimidine -5- bases) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- ethyl-pyrimidine -5- bases) -3- (3- (4- methyl - 1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (4- methyl - 1H- imidazoles -1- bases) -5- (trifluoromethyl) phenyl) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4,6- dimethyl pyrimidine -5- bases) urea；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl Pyrimidine -5- bases) urea；
2- (4- (3- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides；
1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
2- (4- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea groups) -2- (trifluoromethyl) phenyl) -2- methyl propanamides；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- hydroxyl -2,2- diformazans Base propyl group) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((4- ethyl piperazidine -1- bases) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1,6- dihydropyridines - 3- yls) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxyl first Base) cyclopropyl) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) -5- (trifluoromethyl) phenyl) urea；
1- (3- (tert-butyl group) -1- phenyl -1H- pyrazoles -5- bases) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) Urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((4- ethyl piperazidines -1- Base) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (1- amino-2-methyl propane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1, 6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- hydroxyls third Alkane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (3- (1H-1,2,4- triazol-1-yls) -5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -2- fluorophenyls) urea；
1- (4- (1- (dimethylamino) -2- methylpropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyls -6- Oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (the fluoro- 4- of 2- (1- oxo -1,2- dihydro-isoquinoline -4- bases) phenyl) -3- (4- (2- hydroxy propane -2- bases) -3- (three Methyl fluoride) phenyl) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- (hydroxymethyl) rings third Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (2- fluoro- 5- (trifluoromethyl) benzene Base) urea；
1- (4- (tert-butoxy) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- Fluorophenyl) urea；
1- (4- (2- cyano group -2- methyl-propyls) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- isopropoxy -3- (trifluoros Methyl) phenyl) urea；
1- (4- ((2- dicyanopropane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (3- hydroxyl -1- methyl rings Butoxy) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- isopropyl -3- methyl Pyrrolidin-3-yl) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) phenyl) -3- (fluoro- 5- of 2- (trifluoromethyl) Phenyl) urea；
1- (chloro- 5'- ethyoxyls -6'- oxos -1', the 6'- dihydros of 6--[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (1- (hydroxyl first Base) cyclopropyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (6- (2- hydroxy propanes -2- Base) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2,6- difluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl Pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (6- isopropoxy -5- (trifluoros Methyl) pyridin-3-yl) urea；
1- (3- (difluoromethyl) -4- ((3- methy oxetane -3- bases) epoxide) phenyl) -3- (4- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (the fluoro- 4- of 2- (5- hydroxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (5- (methylamino) -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -4- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (4- oxo -4,5- dihydrofuran simultaneously [3,2-c] pyrroles Pyridine -7- bases) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (3- (2- morpholinoes Ethyoxyl) -5- (trifluoromethyl) phenyl) urea；
1- (5'- methoxyl group -6- methyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (6- ((5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) epoxide) pyridin-3-yl) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6- ethyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (fluoro- 6'- oxos -1', the 6'- dihydros of 5'- ethyoxyls -5--[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (6- cyclopropyl -5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -5- methyl -6'- oxos -1', 6'- dihydro-[3,3'- bipyridyls] -6- bases) -3- (4- ((3- methyl Oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- fluoro- 3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- of 2- (5- (3- fluorine propoxyl group) -6- oxo -1,6- dihydropyridines - 3- yls) phenyl) urea；
1- (5- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- methylpyrazine -2- bases) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (azetidine -1- ylmethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (5'- ethyoxyl -6- methoxyl group -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- first Base oxetanes -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (pyrrolidines -1- Ylmethyl) -3- (trifluoromethyl) phenyl) urea；
1- (6- (dimethylamino) -5'- ethyoxyl -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ethyoxyls -3- (trifluoromethyl) phenyl) -3- (4- (1- ethyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorine Phenyl) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (5- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -3- methylpyrazine -2- bases) urea；
1- (5'- ethyoxyl -6- isopropoxy -6'- oxos -1', 6'- dihydro-[2,3'- bipyridyls] -5- bases) -3- (4- ((3- Methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- hydroxyethyls) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((1,3- dimethyl azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyls - 6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- hydroxy-2-methyls third Alkane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2,3- difluorophenyls) -3- (4- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- hydroxy-2-methyls third Alkane -2- bases) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (5- (3- fluorine propoxyl group) -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- isopropoxies -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- hydroxy propanes -2- Base) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- (hydroxymethyl) rings third Epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- ((3- methy oxetane -3- bases) epoxide) phenyl) -3- (4- (4- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (the fluoro- 3- hydroxypropyls of 2,2- bis-) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -2- fluorophenyls) urea；
1- (4- (4- (difluoro-methoxy) -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxygen Azetidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (1- cyano ethyls) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -2- fluorophenyls) urea；
1- (4- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (2- fluoro- 5- (trifluoromethyl) benzene Base) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- hydroxy propanes -2- Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxos third oxygen of -5- Base -1,6- dihydropyridine -3- bases) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (hydroxymethyl) -3- (three Methyl fluoride) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -3- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- (hydroxymethyl) ring fourths Epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- dicyanopropane -2- bases) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) -2- fluorophenyls) urea；
1- (the fluoro- 4- of 2- (5- isopropoxy -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- rings Butane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (2- methyl -4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) Epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (6- oxo -5- propoxyl group -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((fluoro- 2- methyl-props of 1- Alkane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes -3- Base) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (2- hydroxyls -5- (trifluoromethyl) Phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl oxa- ring fourths Alkane -3- bases) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- hydroxyl-oxethyls) -3- (trifluoromethyl) phenyl) urea；
1- (4- ((1,3- dimethyl pyrrolidine -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxygen Generation -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- hydroxy propyloxy groups) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- methyl isophthalic acid H- pyrazoles - 4- yls) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetane -3- bases) oxygen Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (6- ((3- methyl oxa- ring fourths Alkane -3- bases) epoxide) -5- (trifluoromethyl) pyridin-3-yl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (1- methyl cyclobutoxy group) - 3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyl isophthalic acids, 1- dioxies Change Thietane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (ethoxyl methyl) -3- (trifluoromethyl) phenyl) urea；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorobenzene Base) urea；
1- (2- ethyoxyls -4- fluoro- 5- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -2- fluorophenyls) urea；
(S) -1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- fluoropyrrolidines - 1- yls) methyl) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (7- oxo -6,7- dihydrofuran simultaneously [2,3-c] pyridin-4-yl) phenyl) -3- (fluoro- 5- (fluoroforms of 2- Base) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- fluoro- 3- (trifluoromethyl) benzene Base) urea；
1- (4- ((3- methy oxetane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) -3- (4- (6- oxos -1,6- two Pyridinium hydroxide -3- bases) phenyl) urea；
1- (4- cyano group -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorine Phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((1- methoxyl group -2- methyl Propane -2- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- isopropyl phenyls) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) - 3- fluorophenyls) urea；
1- (4- (3,3- difluoros cyclobutoxy group) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -2- fluorophenyls) urea；
4- (3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea groups) -2- (trifluoromethyl) benzene Formamide；
1- (4- isopropoxies -3- (trifluoromethyl) phenyl) -3- (4- (6- oxo -1,6- dihydropyridine -3- bases) phenyl) urea；
1- (4- (5- (difluoro-methoxy) -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- (2- '-hydroxyethoxies Base) -3- (trifluoromethyl) phenyl) urea；
1- (4- (2- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (4- (5- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -2- fluorophenyls) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (the fluoro- 4- of 2- ((3- methyl oxa-s Cyclobutane -3- bases) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) -3- (4- ((3- methyltetrahydrofurans - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- (4- methyl -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3- (4- ((3- methy oxetanes - 3- yls) epoxide) -3- (trifluoromethyl) phenyl) urea；
1- (3- (difluoromethyl) -4- ((3- methy oxetane -3- bases) epoxide) phenyl) -3- (4- (6- oxos -1,6- two Pyridinium hydroxide -3- bases) phenyl) urea；Or
1- (3,4- dichlorophenyls) -3- (4- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -2- fluorophenyls) urea；
Or its pharmaceutically-acceptable salts.
15. compound according to claim 1, it is:
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (fluoro- 4- ((4- of 2- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) urea；
1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- (2- '-hydroxyethoxies Base) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (the fluoro- 4- of 2- ((4- (2- hydroxyethyls) piperazine -1- bases) methyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- (2- hydroxyls Base oxethyl) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methyl Pyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzsulfamide；
1- (4- (1- amino-ethyls) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea；
1- (4- (1- (dimethylamino) ethyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- two Pyridinium hydroxide -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- (2- (pyrroles Alkane -1- bases) ethyl) -3- (trifluoromethyl) phenyl) urea；
1- (3- (2- (dimethylamino) ethyoxyl) -5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) pyrimidine -5- bases) urea；
1- (4- ((dimethylamino) methyl) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) pyrimidine -5- bases) urea；
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (fluoro- 2- first of 1,1,1- tri- Base propane -2- base) isoxazole -3-bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (5- (fluoro- 2- first of 1,1,1- tri- Base propane -2- base) isoxazole -3-bases) urea；
1- (4- ((4- ethyl piperazidine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (4- (2- methoxyl group ethoxies Base) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) pyrimidine -5- bases) -3- (4- ((4- ethyl piperazidines -1- Base) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea；
1- (the fluoro- 4- of 2- ((4- methylpiperazine-1-yls) methyl) -5- (trifluoromethyl)-phenyl) -3- (2- (5- (2- methoxyl group second Epoxide) -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；
1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea；
1- (4- (2- amino-2-methyls propyl group) -3- (trifluoromethyl) phenyl) -3- (2- (4- ethyoxyl -6- oxo -1,6- dihydros Pyridin-3-yl) -4- methylpyrimidine -5- bases) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (4- (2- methoxy ethoxies) -6- oxo -1,6- dihydropyridines -3- Base) -4- methylpyrimidine -5- bases) urea groups) -5- (trifluoromethyl) benzamide；
1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) pyrimidine -5- bases) urea；
N- (2- (dimethylamino) ethyl) -3- (3- (2- (5- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases)-pyrimidine - 5- yls) urea groups) -5- (trifluoromethyl) benzamide；
1- (4- ((dimethylamino) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) -3- (2- (5- ethyoxyl -6- oxos -1,6- Dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) urea；Or
1- (2- (4- ethyoxyl -6- oxo -1,6- dihydropyridine -3- bases) -4- methylpyrimidine -5- bases) -3- (4- ((4- ethyl piperazines Piperazine -1- bases) methyl) -2- fluoro- 5- (trifluoromethyl) phenyl) urea；
Or its pharmaceutically-acceptable salts.
16. pharmaceutical composition, its compound comprising any one of claim 1-15 or pharmaceutically-acceptable salts and pharmaceutically Acceptable excipient.
17. a kind of method for treating IBS, it is included to needs its people's administration effective dosies according to claim Any one of 1-15 compound or pharmaceutically-acceptable salts.
18. a kind of method for the treatment of cancer, it includes appointing according in claim 1-15 to its people's administration effective dose of needs The compound or pharmaceutically-acceptable salts of one.
19. according to any one of claim 1-15 compound or pharmaceutically-acceptable salts, for treating.
20. it is used to treat IBS according to any one of claim 1-15 compound or pharmaceutically-acceptable salts Purposes.
21. it is used for the purposes for the treatment of cancer according to any one of claim 1-15 compound or pharmaceutically-acceptable salts.
22. prepared according to any one of claim 1-15 compound or pharmaceutically-acceptable salts for treating RET mediations Disease medicine in purposes.
23. purposes according to claim 22, wherein the disease is IBS.
24. purposes according to claim 22, wherein the disease is cancer.
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